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31 Cards in this Set

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growth fraction of a tumor
#of diving cells/tumor mass

The higher the growth fraction, the more susceptible the tumor is to chemotherapy
The Log-Kill Hypothesis
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
S-phase specific Drugs
Antimetabolites (like methotrexate) are DNA synthesis inhibitors
M-phase specific Drugs
vinca alkaloids and Paclitaxel interfere with microtubule assembly/disassembly
broad-acting chemotheropeutics
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)
Drug Resistance
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
Toxicity of Chemo
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)
Alkylating agents
cross-link and interfere with DNA replication
Electrophilic drug molecules
react covalently with the nucleophilic atoms in certain cellular constituents (amino, carboxyl groups in nucleic acids and proteins)
Cyclophosphamide (Cytoxan)
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
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
Streptozocin (Zanosar)
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
Cisplatin (Platinol)
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
Methotrexate (MTX)
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
leucovorin rescue
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
Tumor Cell Resistance to MTX (as an example)
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
5-FU
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
Cytarabine
Pyrimidine analog- a cytidine analog

Uses- most important antimetabolite for treatment of AML
6-mercaptopurine
Purine analog

Use- ALL
6-thioguanine
Purine analog

Use- acute non-lymphocytic leukemia
Anthracyclines: Doxorubicin and Daunorubicin
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
Bleomycin
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
Vinca alkaloids (vincristine and vinblastine)
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
Taxol
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
Tamoxifen
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
Aromatase Inhibitors
block the synthesis of estrogen via blocking conversion of androgens by aromatase

Use- estrogen dependent metastatic breast cancer in post-menopausal women
Interferon
Increases activity of various cytotoxic cells

Uses- hairy cell leukemia, CML, and Kaposi’s sarcoma
Interleukin 2
“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
Herceptin
HER2 is over-expressed on the cell surface of tumor cells in 25-30% of women with metastatic breast cancer
Antiangiogenesis agents
bevacizumab (Avastin)
inhibiting VEGF- a growth factor for blood vessels

Use- combo only with FU-5 for metastatic colorectal cancer
Gleevec
inhibits this abl tyrosine kinase activity

Resistance can develop

Use- CML