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31 Cards in this Set
- Front
- Back
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growth fraction of a tumor
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#of diving cells/tumor mass
The higher the growth fraction, the more susceptible the tumor is to chemotherapy |
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The Log-Kill Hypothesis
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A given dose of a certain chemotherapeutic agent can kill a given fraction of tumor cells
Cell-death essentially follows first-order kinetics *Therefore, it is not physically possible to eliminate every cancerous cell with a regimen of chemotherapy. The body must have an intact immune system that can adequately dispose of the remaining tumor cell mass after chemotherapy |
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S-phase specific Drugs
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Antimetabolites (like methotrexate) are DNA synthesis inhibitors
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M-phase specific Drugs
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vinca alkaloids and Paclitaxel interfere with microtubule assembly/disassembly
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broad-acting chemotheropeutics
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Cisplatin acts on all dividing cells (regardless of which phase of the cell-cycle they exhibit)
Bleomycin goes a step further and can kill nondividing cells (in G0) |
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Drug Resistance
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1. Impaired Uptake: drugs may not get into cells
2. Altered Drug Metabolism 3. Altered Drug Targets: mutation in drug binding sites 4. Enhanced DNA repair capacity 5. Multidrug Resistance: upregulated P-glycoprotein can function as an energy-dependent drug efflux pump |
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Toxicity of Chemo
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Damage all rapidly-dividing cell populations
1. hair loss 2. GI Tract – mucosal inflammation, diarrhea 3. Bone Marrow – myelosuppression ‡ low platelets, RBCs, WBCs 4. Reproductive System 5. Nausea and vomiting (Anti-emetics are often prescribed such as ondansetron and metoclopramide) |
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Alkylating agents
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cross-link and interfere with DNA replication
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Electrophilic drug molecules
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react covalently with the nucleophilic atoms in certain cellular constituents (amino, carboxyl groups in nucleic acids and proteins)
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Cyclophosphamide (Cytoxan)
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Nitrogen mustard- Bifunctional alkylating agent
Prodrug - active alkyl groups are formed in the liver by P450 enzymes in addition to acrolein cross-link 2 separate nucleic acids and inhibit DNA replication Use- CLL, non-Hodgkin’s lymphoma, breast and ovarian cancer, and other solid tumors *Unique side-effect: Hemorrhagic cystitis |
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Carmustine (BCNU)
Lomustine (CCNU) |
Nitrosourea- Non-enzymatic (spontaneous) decomposition due to reactive alkylating metabolite which interrupts DNA replication or isocyanate
Use: Primary brain tumors (able to cross BBB) Side Effects: Profound, delayed and cumulative myelo-suppression |
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Streptozocin (Zanosar)
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Nitrosourea- modifies protein, especially DNA repair enzymes so it impairs the repair mechanism
Use: Malignant pancreatic islet cell tumors (insulinomas)- High affinity for beta cells of the islets of Langerhans NOT myelosuppressive |
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Cisplatin (Platinol)
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Analogous to alkylating agent- Binds to intra- and inter-strand crosslinks in cellular DNA leading to inhibition of DNA synthesis
1st line for many solid tumors- Testicular, Ovarian, Bladder, melanoma Side Effects: Nephrotoxicity |
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Methotrexate (MTX)
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a folate analog and acts by irreversible binding to dihydrofolate reductase (DHFR)leading to depletion of tetrahydrofolate, and inhibiting subsequent steps and eventually inhibiting DNA synthesis
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leucovorin rescue
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if you add reduced folate in the form of leucovorin calcium (folinic acid) you will reverse the effects of MTX by bypassing the requirement for tetrahydrofolate
Uses: coriocarcinoma of the uterus, bladder and breast cancer and ALL |
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Tumor Cell Resistance to MTX (as an example)
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MTX must be transported into cells in order to be effective- it requires addition of multiple glutamates to the molecule to become glutamated MTX (active form)
mechanisms for resistance include: 1) impaired transport into tumor cells 2) impaired polyglutamate formation- mutated or defective enzyme for formation of glutamated MTX 3) increased production of DHFR- too many targets for same amount of drug 4) Altered structure of DHFR so that MTX can no longer bind |
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5-FU
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a uracil derivative- inhibits thymidylate sythetase, can also be incorporated into RNA and interfere with RNA function
Uses: Exclusively in solid tumors- breast, colorectal, and gastric cancer. Synergy with other drugs such as MTX. Also used as topical treatment of non-invasive skin cancers |
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Cytarabine
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Pyrimidine analog- a cytidine analog
Uses- most important antimetabolite for treatment of AML |
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6-mercaptopurine
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Purine analog
Use- ALL |
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6-thioguanine
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Purine analog
Use- acute non-lymphocytic leukemia |
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Anthracyclines: Doxorubicin and Daunorubicin
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an anthracene ring that can intercalate into DNA, interfering with synthesis and causing deformation of both DNA and RNA
2) also cause protein associated DNA breaks through effects on topoisomerase II- *main anticancer effect 3) contain quinone moieties which lead to production of reactive free radicals (side effects) Use: most active agent against breast cancer, also Hodgkin’s disease, bladder and ovarian cancer, and gastric carcinoma, acute nonlymphocytic leukemia Unique Side Effects- Cardiac damage |
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Bleomycin
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a group of metal chelating glycopeptides that cause DNA fragmentation through the generation of free radicals
Uses: often use in combo therapy (no myelosuppression) Unique side effects: pulmonary fibrosis |
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Vinca alkaloids (vincristine and vinblastine)
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bind tubulin and inhibit polymerization, destablizing microtubules- cell is arrested in metaphase
Uses- leukemias and lymphomas and some solid tumors- bladder, breast, ovarian, and testicular cancers Side Effects- Vincristine: neuropathy |
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Taxol
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binds to tubulin in the polymerized microtubule and blocks depolymerization- a microtubule stabilizer
Uses-metastatic ovarian cancer, breast cancer, non small cell lung, bladder, head and neck carcinomas |
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Tamoxifen
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hormonal agent- anti-estrogen- competes with estrogen for binding to the estrogen receptor, therefore blocking the estrogen mediated gene expression
Use- estrogen dependent breast cancer |
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Aromatase Inhibitors
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block the synthesis of estrogen via blocking conversion of androgens by aromatase
Use- estrogen dependent metastatic breast cancer in post-menopausal women |
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Interferon
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Increases activity of various cytotoxic cells
Uses- hairy cell leukemia, CML, and Kaposi’s sarcoma |
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Interleukin 2
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“the lymphokine formerly known as T-cell growth factor”
promotes immune cell differentiation and proliferation (T-cells and B-cells)- increased recognition and destruction of tumor cells Uses- renal cell carcinoma, malignant melanoma and colorectal cancer |
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Herceptin
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HER2 is over-expressed on the cell surface of tumor cells in 25-30% of women with metastatic breast cancer
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Antiangiogenesis agents
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bevacizumab (Avastin)
inhibiting VEGF- a growth factor for blood vessels Use- combo only with FU-5 for metastatic colorectal cancer |
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Gleevec
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inhibits this abl tyrosine kinase activity
Resistance can develop Use- CML |
