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158 Cards in this Set
- Front
- Back
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1. What are the three criteria that was established for distinguishing transformed cells from normal cells in culture?
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1. The requirement for serum in the cell culture medium to stimulate cell growth
2. The ability to grow without attachment to a supporting matrix (anchorage dependence) 3. Ability of cells to form tumors when they are injected into mice that lack an immune system |
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2. Chemical and physical alterations in DNA
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An alteration in the chemical structure of DNA, or of the sequence of bases in a gene, is an absolute requirement for the development of cancer.
Can occur via carcinogens, chemotherapeutic agents, radiation, UV light. Each chemical carcinogen or reactant creates a characteristic modification in a DNA base. The DNA damage, if not repaired, introduces a mutation into the next generation when the cell proliferates. |
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3. Carcinogens
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Chemical carcinogens found in the environment and ingested in foods are generally stable lipophilic compounds that must be activated by metabolism in the body to react with DNA.
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4. UV radiation
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Structural alterations in DNA also occur through radiation and through UV light, which causes the formation of pyrimidine dimers. More than 90% of skin cancers occur in sunlight exposed areas.
UV rays derived from the sun induce an increased incidence of all skin cancers, including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma of the skin. |
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5. What wavelength of UV light is most associated with skin CA?
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UVB - (280-320 nm), it forms pyrimidine dimers in DNA.
This type of DNA damage is repaired by nucleotide excision repair aptwhays that require products of at least 20 genes. With excessive exposure to the sun, the nucleotide excision repair pathway is overwhelmed, and some damage remains unrepaired. |
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6. Proto-oncogenes and oncogenes
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Proto-oncogenes are converted to oncogenes by mutations int he DNA that cause a gain in function; that is, the protein can now function better in the absence of the normal activating events.
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7. What are four mechanisms that lead to the conversion of proto-oncogenes to oncogenes?
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1. Radiation and chemical exposure
2. Transposition/translocation of the entire proto-oncogene 3. Amplification of the proto-oncogene 4. Via oncogenic virus that integrates into the host-cell genome |
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8. Radiation and chemical exposure and conversion of proto-oncogenes to oncogenes
Two ways... |
Radiation and chemical carcinogens act by:
1. Causing a mutation in the regulatory region of a gene, increasing the rate of production of the proto-oncogene protein 2. Producing a mutation in the coding portion of the oncogene that results in the synthesis of a protein of slightly different AA composition capable of transforming the cell. |
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9. Transposition/translocation of the entire proto-oncogene and conversion of proto-oncogenes to oncogenes
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The entire proto-oncogene or a portion of it may be transposed or translocated, that is, moved from one position in the genome to another.
In its new location, the proto-oncogene may be expressed under the control of a promoter that is regulated differently than the promoter that normally regulates this gene. This may allow the gene to be expressed ina tissue where it is not normally expressed or at higher-than-normal levels of expression. If only a portion of the proto-oncogene is translocated, it may be expressed as a truncated protein with altered properties, or it may fuse with another gene and produce a fusion protein containing portions of what are normally two separate proteins. The truncated or fusion protein may be hyperactive and cause inappropriate cell growth. |
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10. Amplification of the proto-oncogene and conversion of proto-oncogenes to oncogenes
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The proto-oncogene may be amplified, so that multiple copies of the gene are produced in a single cell. If more genes are active, more proto-oncogene protein will be produced, increasing the growth rate of the cells.
As examples the oncogene N-myc (a cell proliferation transcription factor, related to c-myc) is amplified in some neuroblastomas, and amplification of the erb-B2 oncogene (a growth factor receptor) is associated with several breast CAs. |
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11. Oncogenic virus that integrates into the host-cell genome and conversion of proto-oncogene to oncogene
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If an oncogenic virus infects a cell, its oncogene may integrate into the host-cell genome, permitting production fo the abnormal oncogene protein.
The cell may be transformed and exhibit an abnormal pattern of growth. Rather than inserting an oncogene, a virus may simply insert a strong promoter into the host-cell genome. This promoter may cause increased or untimely expression of a normal proto-oncogene. |
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12. Mutations in DNA repair enzymes
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Repair enzymes are the first line of defense preventing conversion of chemical damage in DNA to a mutation.
DNA repair enzymes are tumor suppressor genes in the sense that errors repaired before replication do not become mutagenic. If DNA repair enzymes are absent, mutations accumulate much more rapidly, and once a mutation develops in a growth-regulatory gene, a cancer may arise. |
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13. Oncogenes
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The mutations in oncogenes that give rise to transformation are usually gain-of-function mutations; either a more active protein is produced or an increased amount of the normal protein is synthesized.
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14. Oncogenes and signal transduction cascades
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All of the proteins in growth-factor signal transduction cascades are proto-oncogenes.
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15. Growth factors and growth factor receptors
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The genes for both growth factors and growth factor receptors are proto-oncogenes.
Growth factors generally regulate growth by serving as ligands that bind to cellular receptors located on the plasma membrane. Binding of ligands to these receptors stimulates a signal transduction pathway in the cell that activates the transcription of certain genes. If too much of a growth-factor receptor is produced, the target cells may respond by proliferating inappropriately. |
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16. How else can growth factor receptors become oncogenic?
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Growth factor receptors may also become oncogenic through translocation or point mutations in domains that affect binding of the growth factor, dimerization, kinase activity, or some other aspect of their signal transmission.
In such cases, the receptor transmits a proliferative signal even though the growth factor normally required to activate the receptor is absent. In other words, the receptor is stuck in the "on" position. |
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17. Signal transduction proteins
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The genes that encode proteins involved in growth factor signal transduction cascades may also be proto-oncogenes.
Consider the monomeric G-protein Ras. Binding of growth factor leads to the activation of Ras. When Ras binds to GTP, it is active, but Ras slowly inactivates itself by hydrolyzing its bound GTP to GDP and Pi. This controls the length of time that Ras is active. Ras is converted to an oncogenic form by point mutations that decrease the activity of the GTPase domain of Ras, thereby increasing the length of time it remains in the active form. |
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18. Active Ras does what?
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Ras, when it is active, activates the serine-threonine kinase Raf (a MAP kinase kinase kinase), which activates MEK ( a MAP kinase kinase), which activates MAP kinase.
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19. Activation of MAP kinase does what...?
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Activation of MAP kinase results in the phosphorylation of cytoplasmic and nuclear proteins, followed by increased transcription of the transcription factor proto-oncogenes myc and fos.
Note that mutations int he genes for any of the proteins that regulate MAP kinase activity, as well as those proteins induced by MAP kinase activation, can lead to uncontrolled cell proliferation. |
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20. What are transcription factors?
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Many transcription factors, such as Myc and Fos, are proto-oncoproteins (the products of proto-oncogenes).
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21. Activation of MAP kinase also does...?
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MAP kinase, in addition to inducing myc and fos, also directly activates the AP-1 transcription factor through phosphorylation.
AP-1 is a heterodimer formed by the protein products of the fos and jun families of proto-oncogenes. The targets of AP-1 activation are genes involved in cellular proliferation and progression through the cell cycle, as are the targets of the myc transcription factor. |
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22. Regulation of C-myc - when is it expressed in the cell cycle?
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The synthesis of the transcription factor C-myc is tightly regulated in normal cells, and it is expressed only during the S phase of the cell cycle.
In a large number of tumor types, this regulated expression is lost, and c-myc becomes inappropriately expressed or overexpressed throughout the cell cycle, driving cells continuously to proliferate. |
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23. What is the net result of alterations in the expression of transcription factors?
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The net results of alteration in the expression of transcription factors is the increased production of the proteins that carry out the processes required for proliferation.
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24. Cell cycle regulation
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The growth of human cells, involving DNA replication and cell division in the cell cycle, is activated by growth factors, hormones, and other messengers. These activators work through cyclins and cyclin dependent kinases (CDK's) that control progression from one phase of the cycle to another.
For quiescent cells to proliferate, they must leave G₀ and enter the G₁ phase of the cell cycle. If the proper sequence of events occurs during G₁, the cells enter the S phase and are committed to DNA replication and cell division. Similarly, during G₂, cells make a commitment to mitotic division. CDK's are made constantly throughout the cell cycle but require binding of a specific cyclin to be active. Different cyclins made at different times in the cell cycle control each of the transitions. |
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25. How is the activity of the cyclin-CDK complex further regulated?
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The activity of the cyclin-CDK complex is further regulated through phosphorylation and through inhibitory proteins called cyclin-dependent kinase inhibitors (CKI's).
CKI's slow cell-cycle progression by binding and inhibiting the CDK-cyclin complexes. CDKs are also controlled through activating phosphorylation by CAK (cyclin-activating kinases) and inhibitory hyperphosphorylation kinases. |
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26. What regulatory proteins are involved in determining whether the cell is ready to pass this checkpoint?
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These regulatory proteins include cdk4 and cdk6, cyclin D, the retinoblastoma gene product (Rb), and a class of transcription factors collectively known as E2F.
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27. How do these regulatory proteins interact with one another?
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In quiescent cells, Rb is complexed with E2F, resulting in inhibition of these transcription factors. Upon growth-factor stimulation the cyclin Ds are induced. They bind to cdk4 and cdk6, converting them to active protein kinases.
One of the targets of cyclin/cdk phosphorylation is the Rb protein. Phosphorylation of Rb releases it from E2F, and E2F is then free to activate the transcription of genes required for entry into S. The Rb protein is a tumor-suppressor gene. |
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28. What are the proteins induced by E2F?
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The proteins induced by E2F include cyclin E, cyclin A, cdc25A, and proteins required to bind at origins of replication to initiate DNA synthesis.
The synthesis of cyclin E allows it to complex with cdk2, forming another active cyclin complex that retains activity into S phase. |
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29. What is one of the major functions of the cyclin E1-cdk2 complex?
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One of the major functions of the cyclin E1-cdk2 complex is hyperphosphorylation of the Rb protein, thereby keeping Rb in its inactive state.
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30. What is the function of Cyclin A?
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Cyclin A also complexes with Cdk2, and it phosphorylates, and inactivates, the E2F family of transcription factors.
This ensures that the signals are not present for extended periods of time. |
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31.What opposes the progression through the cell cycle?
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Progression through the cell cycle is opposed by the CKIs. The CKI's regulating cyclin/cdk expression in the G₁ phase of the cell cycle fall into two categories: the Cip/Kip family and the INK4 family.
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32. What is the function of the Cip/Kip family?
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The Cip/Kip family members (p21, p27, and p57) have a broad specificity and inhibit all cyclin-CDK complexes.
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33. What is the function of the INK4 family?
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The INK4 family, which consists of p15, p16, p18, and p19, are specific for the cyclin D-cdk4/6 family of complexes (INhibitors of cyclin-dependent Kinase-4).
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34. Regulation of the CKI
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The regulation of synthesis of different CKI's is complex, but some is induced by DNA damage to the cell and halts cell cycle progression until the damage can be repaired.
For example, the CKI p21 is a key member of this group that responds to specific signals to block cell proliferation. If the damage cannot be repaired, an apoptotic pathway is selected and the cell dies. |
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35. What are tumor suppressor genes?
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Like the oncogenes, the tumor-suppressor genes encode molecules involved in the regulation of cell proliferation.
The normal function of tumor suppression proteins is generally to inhibit proliferation in response to certain signals such as DNA damage. The signal is removed when the cell is fully equipped to proliferate; the effect of the elimination of tumor suppressor genes is to remove the brakes on cell growth. They affect cell-cycle regulation, signal transduction, transcription, and cell adhesion. The products of tumor suppressor genes frequently modulate pathways that are activated by the products of proto-oncogenes. |
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36. How do tumor suppressor genes contribute to the development of cancer?
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Tumor suppressor genes contribute to the development of cancer when both copies of the gene are inactivated.
This is different from the case of proto-oncogene mutations b/c only one allele of a proto-oncogene needs to be converted to an oncogene to initiate transformation. |
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37. What are the 2 best understood cell cycle regulators that are also tumor suppressors?
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1. Retinoblastoma (rb) gene
2. p53 genes |
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38. What is the retinoblastoma (rb) gene?
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The retinoblastoma gene product, Rb, functions in the transition from G₁ to S phase and regulates the activation of members of the E2F family of transcription factors.
If an individual inherits a mutated copy of the rb allele, there is a 100% chance of that individual developing retinoblastoma, b/c of the high probability that the second allele or rb will gain a mutation. This is considered familial retinoblastoma. Individuals who do not inherit mutatiosn in rb, but who develop retinoblastoma, are said to have sporadic retinoblastoma, and acquire two specific mutations, one in each rb allele or the retinoblast, during their lifetime. |
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39. p53
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The p53 protein is a transcription factor that regulates the cell cycle and apoptosis.
Loss of both p53 alleles is found in more than 50% of human tumors. p53 acts as the "guardian of the genome" by halting replication in cells that have suffered DNA damage and targeting unrepaired cells to apoptosis. |
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40. When does the level of p53 rise?
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In response to DNA damaging mutagens, ionizing radiation, or UV light, the level of p53 rises.
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41.Actions of p53
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p53, acting as a transcription factor, stimulates transcription of p21.
The p21 gene product inhibits the cyclin/CDK complexes, which prevents the phosphorylation of Rb and release of E2F proteins. The cell is thus prevented from entering S phase. |
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42. What else does p53 do?
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p53 also stimulates the transcription of a number of DNA repair enzymes (including GADD45).
If the DNA is successfully repaired, p53 induces its own downregulation, through the activation of the mdm2 gene. If the DNA repair was not successful, p53 activates a number of genes involved in apoptosis, including bax and IGF-BP3. |
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43.WTF is IGF-BP3?!?
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The IGF-BP3 protein product binds the receptor for insulin-like growth factor, which presumably induces apoptosis by blocking the antiapoptotic signaling by growth factors, and the cell enters a growth fact deprivation mode.
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44.Regulators of Ras
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The Ras family of proteins is involved in signal transduction for many hormones and growth factors and is, therefore, oncogenic.
***The activity of these pathways is interrupted by GAPs, which vary among cell types. |
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45. What are GAPs?
Give an example of a GAP |
GTPase-activating proteins
Neurofibromin, the product of the tumor suppressor gene NF-1, is a nervous system specific GAP that regulates the activity of Ras in neuronal tissues. |
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46. How does neurofibromin regulate the activity of Ras in neuronal
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The growth signal is transmitted so long as the Ras protein binds GTP. Binding of NF-1 to Ras activates the GTPase domain of Ras, which hydrolyzes GTP to GDP, thereby inactivating Ras. Without a functional neurofibromin molecule, Ras is perpetually active.
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47. Patch and smoothened co-receptor genes
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These co-receptor genes are an example of tumor suppressors and oncogenes working together.
These co-receptor genes encode the receptor for the hedgehog class of signaling peptides. These co-receptors normally function to control growth during embryogenesis and illustrate the importance of maintaining a balance between oncogenes and tumor-suppressor genes. |
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48.How do the patch and smoothened co-receptor genes work together?
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The Patched receptor protein inhibits Smoothened, its co-receptor protein.
Binding of a hedgehog ligand to Patched releases the inhibition of Smoothened, which then transmits an activating signal to the nucleus, stimulating new gene transcription. |
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49. Which is the onco-gene, and which is the tumor suppressor gene - patch or smoothened?
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Smoothened is a proto-oncogene, and patched is a tumor suppressor gene.
If patched loses its function (definition of a tumor suppressor), then Smoothened can signal the cell to proliferate, even in the absence of a hedgehog signal. Conversely, if smoothened undergoes a gain-of-function mutation (definition of an oncogene), it can signal in the absence of the hedgehog signal, even in the presence of Patched. Inherited mutations in either smoothened or patched will lead to an increased incidence of basal cell carcinoma. |
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50. Cadherins
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The cadherin family of glycoproteins mediates calcium-dependent cell-cell adhesion. Cadherins form intercellular complexes that bind cells together.
They are anchored intracellularly by catenins, which bind to actin filaments. |
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51. E-cadherin
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Loss of E-cadherin expression may contribute to the ability of cancer cells to detach and migrate in metastasis.
Individuals who inherit a mutation in E-cadherin are sharply predisposed to developing diffuse-type gastric cancer. |
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52. What are the two functions of catenins?
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In addition to anchoring cadherins to the cytoskeleton, they also act as transcription factors.
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53. β-catenin
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β-catenin binds to a complex that contains the regulatory protein APC, which activates it for degradation.
When the appropriate signal inactivates APC, β-catenin levels increase, and it travels to the nucleus, where it activates myc and cyclin D1 transcription, leading to cell proliferation. |
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54. What is APC?
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APC is a tumor-suppressor gene. If it is inactivated, ti cannot bind β-catenin and inhibit cell proliferation.
Mutations in APC or proteins that interact with it are found in the vast majority of sporadic human colon cancer. Inherited mutations in APC lead to the most common form of hereditary colon cancer, familial adenomatous polyposis. |
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55. What is phosphatidylserine?
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Phosphatidylserine is a lipid on the inner leaflet of the cell membrane that is exposed on the external surface of apoptotic vesicles.
It is one of the phagocytic markers recognized by macrophages and other nearby phagocytic cells that engulf the apoptotic bodies. |
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56. What can initiate apoptosis?
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Apoptosis can be initiated by injury, radiation, free radicals or other toxins, withdrawal of growth factors or hormones, binding of pro-apoptotic cytokines, or interactions with cytotoxic T-cells in the immune system.
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57. What are the 3 phases of apoptosis?
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1. Initiation phase
2. Signal integration phase 3. Execution phase |
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58. What are caspases?
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Caspases are cysteine proteases that cleave peptide bonds next to an aspartate residue.
They are present in the cell as procaspases, zymogen-type enzyme precursors that are activated by proteolytic cleavage of the inhibitory portion of their polypeptide chain. The different caspases are generally divided into two groups according to their function: initiator caspases, which specifically cleave other pro-caspases; and execution caspases, which cleave other cellular proteins involved in maintaining cellular integrity. |
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59. How are the initiator caspases activated?
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Through two major signaling pathways:
1. The death receptor pathway 2. Mitochondrial integrity pathway |
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60. What do these initiator caspases do?
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They activate the execution caspases, which cleave protein kinases involved in cell adhesion, lamins that form the inner lining of the nuclear envelope, actin and other proteins required for cell structure, and DNA repair enzymes.
They also cleave an inhibitor protein of the endonuclease CAD. With destruction of the nuclear envelope, additional endonucleases also become activated. |
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61. What is the death receptor pathway to apoptosis?
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The death receptors are a subset of TNF-1 receptors, which includes Fas/CD95, TNF-Receptor 1 and Death Receptor 3.
These receptors form a trimer that binds TNF-1 or another death ligand on its external domain and adaptor proteins to its intracellular domain. |
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62. What is the activated TNF-receptor complex?
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The activated TNF-receptor complex forms the scaffold for binding two molecules of procaspase 8, which autocatalytically cleave each other to form active caspase 8.
Caspases 8 and 10 are intiator caspases that activate execution caspases 3, 6, and 7. Caspase 3 also cleaves a Bcl-2 protein, Bid, to a form that activates the mitochondrial integrity pathway to apoptosis. |
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63. What is the mitochondrial integrity pathway to apoptosis?
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Apoptosis is also induced by intracellular signals indicating that cell death should occur.
Examples of these signals included growth-factor withdrawal, cell injury, the release of certain steroids, and an inability to maintain low levels of intracellular calcium. All of these treatments, or changes, lead to release of cytochrome c from the mitochondria. |
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64. Cytochrome c
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Cytochrome c is a necessary protein component of the mitochondrial electron-transport chain that is loosely bound to the outside of the inner mitochondrial membrane. Its release initiates apoptosis.
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65. What is the Apaf/cytochrome c complex?
What does it do? |
In the cytosol, cytochrome c binds Apaf. The Apaf/cytochrome c complex binds caspase 9, an initiator caspase, to form an active complex called the apoptosome.
The apoptosome, in turn, activates execution caspases 3, 6, and 7 by zymogen cleavage. |
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66. What family of proteins integrates pro-death and anti-death signals?
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The Bcl-2 family members are decision makers that integrate pro-death and anti-death signals to determine whether the cell should commit suicide. Both pro-apoptotic and anti-apoptotic members of the Bcl-2 family exist.
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67. What are the two ways that Bcl-2 proteins have of antagonizing death signals?
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1. They insert into the outer mitochondrial membrane to antagonize channel forming pro-apoptotic factors, thereby decreasing cytochrome c release.
2. They may also bind cytoplasmic Apaf so that it cannot form the apoptosome complex. |
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68. What are the two categories of pro-apoptotic family members?
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1. Ion-channel-forming members
2. BH3-only members |
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69. What are the ion-channel-forming members?
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The pro-death ion channel forming members, such as Bax, are very similar to the anti-apoptotic family members, except that they do not contain the binding domain for Apaf.
They have the other structural domains, however, and when they dimerize with pro-apoptotic BH3-only members in the outer mitochondrial membrane, they form an ion channel that promotes cytochrome c release rather than inhibiting it. |
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70. What are the BH3-only members?
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The pro-death BH3-only proteins (e.g. Bim and Bid) contain only the structural domain that allows them to bind to other Bcl-2 family members (the BH3 domain), and not the domains for binding to the membrane or forming ion channels.
Their binding activates the pro-death family members and inactivates the anti-apoptotic members. |
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71. What happens when a cell receives a signal from a pro-death agonist?
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When a cell receives a signal from a pro-death agonist, a BH3 protein like Bid is activated.
The BH3 protein activates Bax, which stimulates release of cytochrome c. |
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72. How is the apoptosome formed?
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Normally, Bcl-2 acts as a death antagonist by binding Apaf and keeping it in an inactive state.
However, at the same time that Bid is activating Bax, Bid also binds to Bcl-2, thereby disrupting the Bcl-2/Apaf complex and freeing Apaf to bind to released cytochrome c to form the apoptosome. |
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73. What is one way that cancer cells bypass apoptosis?
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One of the ways this occurs is through activation of growth-factor-dependent signaling pathways that inhibit apoptosis, such as the PDGF/Akt/BAD pathway.
Nonphosphorylated BAD acts like Bid in promoting apoptosis. Binding of the platelet derived growth factor to its receptor activates PI-3 kinase, which phosphorylates and activates the serine-threonine kinase Akt). |
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74. Activation of Akt results in ...?
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Activation of Akt results in the phosphorylation of the pro-apoptotic BH3-only protein BAD, which inactivates it.
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75. What is one of the features of neoplastic transformation?
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The loss of growth-factor dependence for survival.
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76. MAP kinase and apoptosis
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The MAP kinase pathway is also involved in regulating apoptosis and sends cell-survival signals.
MAP kinase kinase phosphorylates and activates another protein kinase known as RSK. Like Akt, RSK phosphorylates BAD and inhibits its activity. Thus, BAD acts as a site of convergence for the PI-3 kinase/Akt and MAP kinase pathways in signaling cell survival. |
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77. What genes mutations can be responsible for basal cell carcinoma?
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Patched and Smoothened are the receptor and co-receptor for the signaling peptide, sonic hedgehog.
Either mutation of smoothened, or inactivation of patched, can give rise to basal cell carcinoma. |
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78. What 3 viruses are associated with cancer?
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Three RNA retroviruses are associated with the development of cancer in humans:
1. HTLV-1 2. HIV 3. HepC |
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79. HTLV-1
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HTLV-1 causes adult T-cell leukemia.
The HTLV-1 genome encodes a protein Tax, which is a transcriptional coactivator. The cellular proto-oncogenes c-sis and c-fos are activated by Tax, thereby altering the normal controls on cellular proliferation and leading to malignancy. Thus, tax is a viral oncogene without a counterpart in the host-cell genome. |
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80. HIV
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The HIV genome encodes a protein, Tat, a transcription factor that activates transcription of the IL-6 and IL-10 genes in infected T-cells.
IL-6 and IL-10 are growth factors that promote proliferation of T-cells, and thus their increased production may contribute to the development of non-Hodgkin's lymphoma. Tat can also be released from infected cells and act as an angiogenic growth factor. This property is thought to contribute to the development of Kaposi sarcoma. |
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81. DNA viruses
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3 DNA families, SV40, papilomavirus, and adenovirus, encode proteins that inactivate pRb and p53.
By interfering with the cell cycle checkpoints, the oncoproteins increase the chance that mutations in oncogenes and tumor-suppressor genes will be incorporated into the genome of infected cells. The Epstein-Barr virus encodes a Bcl-2 protein that restricts apoptosis of the infected cell. |
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82. Bleeding problems in leukemia
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Patients with leukemia experience a variety of hemorrhagic manifestations caused by a decreased number of platelets.
B/c of the uncontrolled proliferation of WBCs within the limited space of the marrow, the normal platelet precursors (the megakaryocytes) int he marrow are squeezed or crowded and fail to develop into mature platelets. Consequently, the number of mature platelets in the circulation falls, and a thrombocytopenia develops. |
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83. Moles
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Moles (nevi) are tumors of the skin.
They are formed by melanocytes that have been transformed from highly dendritic single cells interspersed among other skin cells to round oval cells that grow in aggregates or nests. |
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84. What is Burkitt lymphoma?
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Burkitt lymphoma is a general name for a number of types of B-cell malignancies, resutls from a traslocation between chromosome 8 & 14.
The translocation of genetic material moves the proto-oncogene transcription factor c-myc to chromosome 14. The translocated gene is now under the control of the promoter regions for the Ig heavy-chain gene, which leads to inappropriate overexpression of c-myc. The result may be uncontrolled cell proliferation and tumor development. All subtypes of Burkitt lymphoma contain this translocation. Epstein-Barr virus infection of B-cells is also associated with certain types of Burkitt lymphoma. |
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85. CML & the Philadelphia chromosome
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The Philadelphia chromosome results from a reciprocal translocation between the long arms of chromosome 9 & 22.
As a consequence, a fusion protein is produced that contains the N-terminal region of the Bcr protein from chromosome 22 and the C-terminal region of the Abl protein from chromosome 9. Abl is a proto-oncogene, and the resulting fusion protein (Bcr-Abl) has lost its regulatory region and is constitutively active. When ti is active, ABL stimulates the Ras pathway of signal transduction, leading to cell proliferation. |
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86. BRCA1 and BRCA2 genes and cancers
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BRCA1 mutations are also linked to ovarian cancer and BRCA2 mutations are not.
BRCA2 mutations have been linked to pancreatic cancer, whereas BRCA1 mutations have not. Men with inherited BRCA2 mutations develop breast CA, but men who carry BRCA1 mutations do not. |
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87. HER2
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The gene for the human epidermal growth-factor receptor (HER2) is overexpressed in 10-20% of breast CAs.
When this gene is overexpressed, the prognosis for recovery is poor, as the patients display shorter disease free intervals, increased risks for metastasis, and a resistance to therapy. |
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88. Herceptin
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A drug has been developed that recognizes and blocks the receptor's action (herceptin, a monoclonal antibody with specificity to the HER2 protein).
However, not all tumor that over-express HER2 are responsive to herceptin. |
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89. What genes play a role in development of malignant melanoma?
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10% of melanomas tend to run in families. Some of the suspected melanoma-associated genes include the tumor-suppressor gene p16 (an inhibitor of cdk 4) and CDK4.
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90. What happens when Bcl-2 is mutated?
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When Bcl-2 is mutated, and oncogenic, it is usually over-expressed for example, in follicular lymphoma and CML.
Overexpression of Bcl-2 disrupts the normal regulation of pro and anti apoptotic factors and tips the balance to an antiapoptotic stand. This leads to an inability to destroy cells with damaged DNA, such that mutations can accumulate within the cell. Bcl-2 is also a multidrug resistant protein and if it is overexpressed it will block the induction of apoptosis by antitumor agents by rapidly removing them from the cell. |
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91. What is Gleevec?
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A new treatment for CML - the fusion protein Bcr-Abl is found only in transformed cells that express the Philadelphia chromosome and not in normal cells.
Gleevec was designed to specifically bind to and inhibit only the active site of the fusion protein and not the normal protein. Gleevec was successful in blocking Bcr-Abl function, thereby stopping cell proliferation and in some cells inducing apoptosis, so the cells would die. B/c normal cells do not express the hybrid protein, they were not affected by the drug. |
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92. What were some problems with Gleevec?
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The problem with this treatment is that some patients suffered relapses, and when their Bcr-Abl proteins were studied it was found that in some patients the fusion protein has a single AA substitution near the active site that prevented Gleevec from binding to the protein.
Other patients has an amplification of the Bcr-Abl gene product. |
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93. What mutations are associated with malignant melanomas?
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1. ras - gain of function in growth signal transduction oncogene
2. p53 (loss) 3. p16 (loss) 4. Cdk4 (gain) 5. Cadherin/β-catenin regulation (loss) |
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94. What are inhibitors of thymidylate synthase?
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Thymidylate (dTMP) is synthesized by the methylation of 2'-deoxyuridylate (dUMP). This reaction, which is catalyzed by thymidylate synthase, requires MTHF as a cofactor.
Inhibitors of thymidylate synthase thereby decrease cellular availability of dTMP and cause "thymineless" cell death. |
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95. What are the three inhibitors of thymidylate synthase?
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1. Fluorouracil (5-FU)
2. Capecitabine 3. Pemetrexed |
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96. What is 5-Fluorouracil (5-FU)?
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5-Fluorouracil inhibits DNA synthesis, primarily by interfering with the biosynthesisis of thymidylate. 5-FU is first converted to 5-fluoro-2'-deoxyuridylate (FdUMP) by the same pathways that convert uracil to dUMP. FdUMP then inhibits thymidylate synthase by forming, together with MTHF, a stable, covalent ternary enzyme-substrate-cofactor complex.
5-FU can also be metabolized to floxuridine triphosphate (FUTP), which can be incorporated into mRNA in place of uridylate and can thereby interfere with RNA processing. |
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97. 5-Fluorouracil (5-FU)
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MOA: Inhibits thymidylate synthase, thereby decreasing cellular availability of dTMP and causing "thymineless" cell death
PURPOSE: Breast CA, GI cancers, Skin CA (topical) ADVERSE: Coronary atherosclerosis, thrombophlebitis, GI ulcer, myelosuppression, cerebellar syndrome, visual changes, stenosis of lacrimal system; Alopecia, rash, pruritus, photosensitivity, GI disturbance, stomatitis, headache CONTRA: Severe bone marrow depression, poor nutritional state, serious infection, Dihodropyrimidine dehydrogenase deficiency, pregnancy NOTES: In addition to inhibiting thymidylate synthase, 5-FU interferes with protein synthesis after the drug metabolite FUTP is incorporated into mRNA. *Folinic acid can be used to potentiate the action of 5-FU. |
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98. What is capecitabine?
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Capecitabine is an orally available prodrug of 5-FU. It is absorbed across the GI mucosa and converted by a series of three enzymatic reactions to 5-FU.
Capecitabine is approved for the treatment of metastatic colorectal cancer and as second line therapy in metastatic breast CA. |
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99. Capecitabine
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MOA: *Orally available prodrug form of 5-FU* Inhibits thymidylate synthase, thereby decreasing cellular availability of dTMP and causing "thymineless" cell death
PURPOSE: Metastatic colorectal CA; breast CA ADVERSE: Coronary atherosclerosis, thrombophlebitis, GI ulcer, myelosuppression, cerebellar syndrome, visual changes, stenosis of lacrimal system; Alopecia, rash, pruritus, photosensitivity, GI disturbance, stomatitis, headache CONTRA: Dihodropyrimidine dehydrogenase deficiency, severe renal impairment |
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100. What is pemetrexed?
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Pemetrexed is a folate analogue that, similar to endogenous folate and the dihydrofolate reductase (DHFR) inhibitor methotrexate, is transported into cells by the reduced folate carrier and polyglutamated by the intracellular enzyme folylpolyglutamate synthase.
Polyglutamated pemetrexed is a potent inhibitor of thymidylate synthase and a much weaker inhibitor of DHFR. |
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101. Pemetrexed
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MOA: Pemetrexed is a folate analogue that, after intracellular modification, inhibits thymidylate synthase by binding to the methylenetetrahydrofolate (cofactor) site on the enzyme
PURPOSE: Nonsmall cell lung CA; Malignant pleural mesothelioma (in combo w/cisplatin) ADVERSE: Myelosuppression, angina, MI, stroke, thrombophlebitis, liver damage, bullous skin rash; fatigue, nausea, vomiting, diarrhea, stomatitis CONTRA: Hypersensitivity of pemetrexed and severe renal impairment NOTES: ***To reduce toxicity to normal cells, patients treated with pemetrexed are also given folic acid and vitamin B12 supplementation. |
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102. 5-FU vs. pemetrexed
How are they different? |
The 5-FU derivative 5-FdUMP inhibits thymidylate synthase by binding to the dUMP [substrate] on the enzyme, whereas pemetrexed inhibits thymidylate synthase by binding to the MTHF [cofactor] on the enzyme.
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103. What are inhibitors of purine metabolism? What are their names?
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These are drug metabolites that inhibit IMPDH and other synthetic enzymes, thereby interfering with AMP and GMP synthesis.
1. 6-Mercaptopurine (6-MP) 2. Azathioprine 3. Pentostatin |
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104. What is 6-Mercaptopurine (6-MP)?
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6-MP is an inosine anologue that inhibits interonversions among purine nucleotides.
6-MP contains a sulfur atom in place of the keto group at C6 of the purine ring. After its entry into cells, MP is converted by HGPRT to the nucleotide form, 6-thioinosine-5'-monophosphate (T-IMP). |
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105. T-IMP is thought to inhibit purine nucleotide synthesis by several mechanisms - what are these 3 mechanisms?
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1. T-IMP inhibits the enzymes that convert IMP to AMP and GMP, including inosine monophosphate dehydrogenase (IMPDH).
2. T-IMP (as well as AMP and GMP) is a feedback inhibitor of the enzyme that synthesizes phosphoribosylamine, which is the first step in purine nucleotide synthesisi. Both of these mechanisms lead to marked decreases in the cellular levels of AMP and GMP, which are essential metabolites for DNA synthesis, RNA synthesis, energy storage, cell signaling, and other functions. |
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106. 6-Mercaptopurine (6-MP) and Azathioprine
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MOA: Drug metabolites inhibit IMPDH and other synthetic enzymes, thereby interfering w/AMP and GMP synthesis
PURPOSE: ALL, AML, Crohn's disease ADVERSE: Pancreatitis, myelosuppression, hepatotoxicity, infection, gastritis CONTRA: Pregnancy NOTES: Effectiveness and toxicity increased by allopurinol |
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107. Azathioprine
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MOA: Azathioprine is a less toxic prodrug of 6-MP. This prodrug is nonenzymatically converted to 6-MP in tissues. Drug metabolites inhibit IMPDH and other synthetic enzymes, thereby interfering w/AMP and GMP synthesis
PURPOSE: Immunosuppression in renal transplantation, rheumatoid arthritis, inflammatory bowel disease ADVERSE: Pancreatitis, myelosuppression, hepatotoxicity, infection, gastritis CONTRA: Pregnancy NOTES: Used for immunosuppression of autoimmune diseases. |
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108. Allopurinol and 6-MP
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6-MP effectiveness and toxicity is increased by allopurinol.
Allopurinol inhibits xanthine oxidase, thereby preventing the oxidation of 6-MP to its inactive metabolite 6-thiouric acid. Coadministration of allopurinol with 6-MP allows the dose of 6-MP to be reduced by two-thirds. |
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109. What is pentostatin?
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Pentostatin is a selective inhibitor of adenosine deaminase (ADA). The drug is a structural analogue of the intermediate in the reaction catalyzed by ADA and binds to the enzyme with high affinity.
The resulting inhibition of ADA causes an increase in intracellular adenosine and 2'-deoxyadenosine levels. The increased adenosine and 2'deoxyadenosine have multiple effects on purine nucleotide metabolism. In particular, 2'-deoxyadenosine irreversibly inhibits S-adenosylhomocysteine hydrolase, and the resulting increase in intracellular S-adenosylhomocysteine is toxic to lymphocytes. |
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110. Pentostatin
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MOA: Selective inhibitor of adenosine deaminase (ADA)
PURPOSE: Hairy cell leukemia; T-cell lymphoma ADVERSE: Cardiac arrhythmia, heart failure, myelosuppression, hepatotoxicity, pulmonary toxicity, rash, shaking chills, vomiting, myalgia, URI, fever CONTRA: Hypersensitivity |
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111. What is an inhibitor of ribonucleotide reductase?
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Hydroxyurea.
It inhibits ribonucleotide reductase by scavenging a tyrosyl radical at the active site of the enzyme. In the absence of this free radical, ribonucleotide reductase is unable to convert nucleotides to deoxynucleotides, and DNA synthesis is thereby inhibited. |
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112. Hydroxyurea
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MOA: Inhibit ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides
PURPOSE: Hematologic malignancies; head and neck CA; melanoma, ovarian CA, sickle cell anemia (adults only) ADVERSE: Myelosuppression; secondary leukemia w/long term use; GI toxicity, skin ulceration CONTRA: Severe bone marrow depression NOTES: Reduces tyrosine free radical critical to mechanism of action of ribonucleotide reductase. *In sickle cell anemia, hydroxyurea is thought o act by increasing HbF. |
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113. What are the names of the 6 purine and pyrimidine analogues that are incorporated into DNA?
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1. Thioguanine
2. Fludarabine phosphate 3. Cladribine 4. Cytarabine (araC) 5. Azacytidine 6. Gemcitabine |
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114. How do these drugs work?
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These drugs are substrates for the vaious pathways of nucleotide metabolism, including ribosylation, ribonucleotide reduction, and nucleoside and nucleotide phosphorylation.
The sugar tri-phosphate forms of these drugs can then by incorporated into DNA. Once incorporated into DNA, these compounds disrupt the structure of DNA, resulting in DNA chain termination, DNA strand breakage, and inhibition of cell growth. |
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115. Thioguanine
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MOA: Guanine analogue. Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death
PURPOSE: AML ADVERSE: Myelosuppression, hyperuricemia, intestinal perforation, hepatotoxicity, infection, GI disturbance CONTRA: Prior resistance to thioguanine or mercaptopurine |
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116. Fludarabine phosphate
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MOA: Fluorinated purine nucleotide analogue. Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death
PURPOSE: B-cell CLL; NHL ADVERSE: Aplasia of skin, autoimmune hemolytic anemia, myelosuppression, neurotoxicity, pneumonia, infection; edema, GI disturbance, asthenia, fatigue CONTRA: Hypersensitivity NOTES: Structurally related to the antiviral agent vidarabine. |
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117. Cladribine
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MOA: Purine analogue. Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death
PURPOSE: Hairy cell leukemia, MS ADVERSE: Febrile neutropenia, myelosuppression, neurotoxicity, infection; rash, injection site reaction, nausea, headache CONTRA: Hypersensitivity |
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118. What is Cytarabine (araC)?
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Cytarabine (araC) is a cytidine analogue that is metabolized to araCTP.
araCTP competes with CTP for DNA polymerase, and incorporation of araCTP into DNA results in chain termination and cell death. Cytarabine is used to induce and maintain remission in acute myelocytic leukemia; it is especially effective for this indication when combined with an anthracycline. |
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119. Cytarabine (araC)
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MOA: Cytidine analogue. Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death
PURPOSE: ALL, AML, CML, meningeal leukemia, Hodgkin's disease, NHL ADVERSE: Myelosuppression, neuropathy, nephrotoxicity, liver dysfunction, infection; thrombophlebitis, rash, hyperuricemia, GI disturbance, ulcers of the mouth or anus CONTRA: Hypersensitivity |
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120. Azacytidine
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MOA: Cytidine analogue. Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death
PURPOSE: Myelodysplastic syndrome ADVERSE: Myelosuppression, renal failure; peripheral edema, GI disturbance, hepatic coma, lethargy, cough, fever CONTRA: Advanced malignant hepatic tumors |
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121. Gemcitabine
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MOA: Cytidine analogue. Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death
PURPOSE: Pancreatic CA; nonsmall cell lung CA, breast CA, ovarian CA, bladder CA, sarcoma, Hodgkin's disease ADVERSE: Myelosuppression, febrile neutropenia, pulmonary toxicity, hepatotoxicity, HUS; fever, GI disturbance, liver enzyme elevation, edema, rash, paresthesias CONTRA: Hypersensitivity to gemcitabine and pregnancy |
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122. What are the 11(!) agents that directly modify DNA structure: alkylating agents?
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1. Cyclophosphamide
2. Mechlorethamine 3. Melphalan 4. Estramustine 5. Chlorambucil 6. Mitomycin 7. Thiotepa 8. Carmustine 9. Dacarbazine 10. Procarbazine 11. Altretamine |
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123. How do alkylating agents work?
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Alkylating agents are electrophilic molecules that are attacked by nucleophilic sites on DNA, resulting in the covalent attachment of an alkyl group to the nucleophilic site.
Alkylating agents typically have two strong leaving groups, and this confers the ability to bis-alkylate, enabling the agent to crosslink the DNA molecule either to itself or to proteins. ***Bis-alkylation (crosslinking) seems to be the major mechanisms of cytotoxicity. |
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124. Cyclophosphamide
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MOA: Covalently bind DNA, often crosslink to DNA or associated proteins
PURPOSE: Autoimmune diseases; leukemias and lymphomas; advanced mycosis fungoides, neuroblastoma, ovarian CA, retinoblastoma, breast CA, malignant histiocytosis ADVERSE: Myelosuppression, cardiomyopathy, Stevens-Johnson syndrome, hemorrhagic cystitis, azoospermia, interstitial pneumonia, infection; alopecia, GI disturbance, leukopenia, amenorrhea CONTRA: Severely depressed bone marrow function |
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125. Therapeutic considerations for cyclophosphamide
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Cyclophosphamide is a non-reactive prodrug that requires activation by the hepatic cytochrome P450; this agent can be administered either orally or via IV.
***Acrolein, a metabolite of cyclophosphamide, causes hemorrhagic cystitis; this adverse effect can be prevented by coadministration with mesna.*** |
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126. Mechlorethamine, Melphalan, Estramustine, Chlorambucil, Mitomycin, Thiotepa, Carmustine, Dacarbazine, Procarbazine, Altretamine
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MOA: Covalently bind DNA, often crosslink to DNA or associated proteins
PURPOSE: Leukemia and Hodgkin's disease (mechlorethamine); Lymphoma (melphalan); Prostate CA (estramustine); Leukemia (chlorambucil); Gastric and pancreatic CA (mitomycin); Bladder CA (carmustine); Hodgkins disease (dacarbazine, procarbazine); Ovarian CA (altreatmine) ADVERSE: Same as cyclophosphamide CONTRA: Presence of known infectious disease (mechlorethamine); active thrombophlebitis or thromboembolic disorder (estramustine); coagulation disorder or renal impairment (mitomycin); hepatic, renal or bone marrow dysfunction (thiotepa); severe bone marrow depression (procarbazine, altretamine); severe neurologic toxicity (altretamine) |
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127. Mechlorethamine
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Mechlorethamine is used to treat leukemia and Hodgkin's disease.
Do not give to patients in the presence of a known infectious disease. |
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128. Melphalan
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Melphalan is used to treat lymphoma
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129. Estramustine
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Estramustine is used to treat prostate CA.
Do not give to patients with active thrombophlebitis or thromboembolic disorder. |
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130. Chlorambucil
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Chlorambucil is used to treat leukemia.
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131. Mitomycin
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Mitomycin is used to treat gastric and pancreatic CA
Do not give to patients with a coagulation disorder or renal impairment. |
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132. Thiotepa
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Thiotepa is used to treat bladder CA.
Do not give to patients with hepatic, renal or bone marrow dysfunction. *This medication is instilled directly in the bladder. |
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133. Carmustine
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Carmustine is used to treat brain cancer.
***Carmustine is a nitrosurea that attaches a carbamoyl group to target proteins. Requires bioactivation. |
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134. Dacarbazine
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Dacarbazine is used to treat Hodgkin's disease and has some activity in treating melanoma and sarcomas.
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135. Procarbazine
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Procarbazine is used to treat Hodgkin's disease.
Do not give to patients with severe bone marrow depression. |
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136. Altretamine
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Altretamine is used to treat Hodgkin's disease and refractory ovarian cancer.
Do not give to patients with severe bone marrow depression or severe neurologic toxicity. |
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137. What is O⁶-alkylguanine-DNA alkyltransferase?
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This enzyme prevents permanent DNA damage by removing alkyl adducts to the O⁶ position of guanine before DNA crosslinks are formed.
***Increased expression of this enzyme in neoplastic cells is associated with resistance to alkylating agents.*** |
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138. Acrolein and ifosfamide
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Acrolein is a byproduct of the activation of cyclophosphamide or its analogue ifosfamide. These can be produce hemorrhagic cystitis b/c of accumulation and concentration in the bladder.
This toxicity can be treated by using the sulfhydryl-containing molecule mesna, which is also concentrated in the urine and rapidly inactivates the acrolein. |
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139. What are the names of the agents that directly modify DNA structure: platinum compounds?
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These agents crosslink intrastrand guanine bases.
Includes: 1. Cisplatin 2. Carboplatin 3. Oxaliplatin |
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140. Cisplatin and carboplatin
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MOA: Crosslink intrastrand guanine bases
PURPOSE: Genitourinary CA, lung CA ADVERSE: Nephrotoxicity (cisplatin); myelosuppression, peripheral neuropathy, ototoxicity, electrolyte imbalance CONTRA: Severe bone marrow depression, renal or hearing impairment NOTES: Cisplatin can be injected intraperitoneally for treatment of ovarian cancer. ***Coadministration of amifostine with cisplatin can limit nephrotoxicity.*** |
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141. Oxaliplatin
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MOA: Crosslink intrastrand guanine bases
PURPOSE: Colorectal CA ADVERSE: Acute and persistent neurotoxicity, myelosuppression, colitis, hepatic dysfunction; GI disturbance, back pain, cough, fever CONTRA: Hypersensitivity NOTES: *Induces a unique acute neurotoxicity that is exacerbated by exposure to cold temperatures. |
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142. What is bleomycin?
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The bleomycins, a family of natural glycopeptides synthesized by a species of Streptomyces, have prominent cytotoxic activity.
Bleomycin binds DNA and chelates Iron (II), leading to the formation of free radicals that cause single and double strand DNA breaks. In chelating iron, bleomycin forms a heme-like ring which generates oxidative intermediates. |
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143. Bleomycin
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MOA: Bleomycin binds oxygen and chelates Iron (II), binds DNA and leads to double strand DNA breaks via generation of oxidative intermediates
PURPOSE: Testicular CA; Hodgkin disease; NHL, Squamous cell CA ADVERSE: ***Pulmonary fibrosis, vascular disease, MI, stroke, Raynaud's hepatotoxicity, nephrotoxicity, rare myelosuppression; alopecia, rash, hyperpigmentation, skin tenderness, GI disturbance, stomatitis CONTRA: Hypersensitivity NOTES: *Effects on pulmonary function are dose-limiting and irreversible |
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144. What are topoisomerase inhibitors?
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These agents damage DNA by exploiting the natural nuclease/ligase function of topoisomerases.
They inhibit topoisomerase I or topoisomerase II, leading to DNA strand breakage. These include: 1. Camptothecins (Irinotecan and topotecan) 2. Anthracyclines 3. Epipodophyllotoxins 4. Amsacrine |
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145. Irinotecan and topotecan
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MOA: Irinotecan and topotecan target topoisomerase I. They act by stabilizing this nicked DNA complex and preventing topoisomerase I from religating the strand break.
PURPOSE: Colorectal CA (irinotecan), small cell lung CA, cervical CA, ovarian CA (topotecan) ADVERSE: Life-threatening diarrhea, myelosuppression, febrile neutropenia, liver dysfunction, interstitial lung disease, alopecia, esoinophilia CONTRA: Severe bone marrow depression NOTES: *Action is specific to S phase |
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146. What are the anthracyclines?
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Anthracyclines are natural antitumor antibiotics isolated from a species of the fungus Streptomyces, and are among the most clinically useful cytotoxic cancer chemotherapeutic agents.
***They act on topoisomerase II, resulting in DNA lesions such as strand scission and, ultimately, in cell death. 1. Doxorubicin 2. Daunorubicin 3. Epirubicin 4. Etoposide 5. Amsacrine |
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147. Doxorubicin, Daunorubicin, Epirubicin, Etoposide, Amsacrine
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MOA: Inhibit topoisomerase II, resulting in DNA lesions such as strand scission and, ultimately, in cell death.
PURPOSE: Leukemias, lymphomas, breast CA, bladder CA, thyroid CA, GI CA, nephroblastoma, osteosarcoma, ovarian CA, small cell CA of lung, soft tissue sarcoma (doxorubicin); ALL and AML (daunorubicin); Breast CA (epirubicin) ADVERSE: Heart failure (especially doxorubicin); myelosuppression; alopecia, rash, GI disturbance CONTRA: Pre-existing heart failure; severe bone marrow depression, severe hepatic dysfunction (epirubicin) NOTES: *Action is specific to G2 phase; Excreted in bile so reduce dose in pts w/hepatic dysfunction |
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148. Etoposide and teniposide
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MOA: Etoposide and teniposide inhibits topoisomerase II, leading to DNA strand breakage
PURPOSE: Testicular and lung CA, leukemia (etoposide); ALL, NHL (teniposide) ADVERSE: Heart failure, myelosuppression; alopecia, rash, GI disturbance CONTRA: Hypersensitivity NOTES: *Action is specific to late S and G2 phases |
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149. Amsacrine
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MOA: Amsacrine inhibits topoisomerase II-mediated regulation of double-strand DNA breaks. This distorts the double helix, producing DNA-protein crosslinks, and creates both single and double strand DNA lesions.
PURPOSE: Recurrent leukemia; ovarian CA ADVERSE: ECG changes including QT prolongation, paralytic ileus, myelosuppression, convulsion, azoospermia, hepatotoxicity, alopecia, GI disturbance CONTRA: Hypersensitivity |
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150. What is dexrazoxane?
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Cardiotoxicity of doxorubicin can be reduced by coadministration of dexrazoxane, which is though to inhibit free radical formation by chelating intracellular iron and preventing iron-mediated free radical generation.
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151. What are the agents that inhibit microtubule polymerization?
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Drugs that inhibit microtubule function are preferentially toxic to M-phase cells.
Vinca alkaloids bind to β-tubulin on a portion of the molecule that overlaps with the GTP binding domain. This prevents microtubule polymerization Includes: vinblastine and vincristine |
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152. Vinblastine
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MOA: Bind tubulin subunits and prevent microtubule polymerization
PURPOSE: Metastatic testicular CA, lymphoma, AIDS-related Kaposi sarcoma, breast CA, choriocarcinoma, malignant histiocytosis, mycosis fungoides ADVERSE: ***Myelosuppression, hypertension, neurotoxicity, azoospermia, alopecia, bone pain, GI disturbance CONTRA: Bacterial infection; significant granulocytopenia NOTES: ****Bone marrow suppression is dose limiting*** |
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153. Vincristine
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MOA: Bind tubulin subunits and prevent microtubule polymerization
PURPOSE: Leukemias; Hodgkin's disease, NHL, rhabdomyosarcoma, nephroblastooma ADVERSE: ***Peripheral neuropathy, myopathy, myelosppression, alopecia, GI disturbance, diplopia CONTRA: Charcot-Marie-Tooth syndrome; intrathecal use NOTES: ***Peripheral neuropathy is dose limiting |
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154. What are the inhibitors of microtubule depolymerization?
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The taxanes, which include paclitaxel and docetaxel, are natural products originally derived from the bark of the western yew tree.
Taxanes bind to the β-tubulin subunit of microtubules at a site distinct from the vinca alkaloid binding site. ***Unlike the vinca alkaloids, taxanes promote microtubule polymerization and inhibit depolymerization.*** Stabilization of the microtubules in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis. |
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155. Paclitaxel and albumin-bound paclitaxel (Abraxane)
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MOA: Bind polymerized tubulin and inhibit microtubule depolymerization
PURPOSE: Ovarian CA; breast CA; nonsmall cell lung CA, AIDS-related Kaposi's sarcoma ADVERSE: Myelosuppression, pulmonary toxicity, severe hypersensitivity reaction, myopathy, ***peripheral neuropathy***; alopecia, GI disturbance, arthralgia CONTRA: Severe neutropenia NOTES: ***Peripheral neuropathy is dose limiting |
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156. Docetaxel
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MOA: Bind polymerized tubulin and inhibit microtubule depolymerization
PURPOSE: Breast CA, gastric CA, prostate CA, nonsmall cell lung CA ADVERSE: *Myelosuppression*, Stevens-Johnson syndrome, fluid retention syndrome leading to severe edema, neuropathy, hepatotoxicity, colitis, alopecia, GI disturbance, asthenia, fever CONTRA: Severe neutropenia NOTES: *Myelosuppression is dose limiting |
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157. What are PARP1 inhibitors?
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PARP1 inhibitors are thought to represent promising new agents in the treatment of BRCA1- or BRCA2-deficient breast or ovarian CA, and may be effective in other tumors in which the DNA damage response is compromised.
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158. Telomerase inhibitors
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The observation that telomerase is expressed in most CA cells and is a key component of the process of immortalization highlights this enzyme as an important target in future cancer therapy.
Although telomerase is expressed to some degree in stem cells and in normally cycling cells, most normal cells lack telomerase expression. Therefore, the dependency of tumor cells on the immortalized state could provide telomerase inhibitors with a favorable therapeutic index. |
