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Flashcards in Cancer II Deck (29):
1

What do most chemotherapeutic agents interfere with? Which cells are more sensitive to chemo?

Cell proliferation and/or induce apoptosis;
rapidly dividing cancer cells more so than normal cells

2

What is the log-kill hypothesis? What is the relationship between cell viability and drug concentration?

Given dose of drug kills CONSTANT FRACTION of cells rather than CONSTANT NUMBER of cells (first order); cell via decreases with increased drug concentration

3

What are the principles of combination therapy?

1. Drugs should have individual anticancer actions
2. Drugs ought to act by different mech's
3. Ideally have synergistic or additive effects
4. Consider different dose-limiting toxicities
5. Give several cycles of treatment

4

What are advantages of chemo?

1. Provide max cell killing with less toxicity
2. Effective against HETEROGENEOUS pop's present in tumors
3. Reduce chance of development of resistant clones

5

Limitations of chemo?

A. Drug resistance in long term (decreased cell uptake, abnormal transport of drug, increased cellular inactivation, altered target protein, reduced affinity for drug, enhanced repair of DNA damage)
B. Toxicity (neutropenia, thrombocytopenia, anemia, nausea/vomiting, stomatitis, alopecia (hair loss), leukemia/myelodysplasia

6

Regarding their actions on the cell cycle, how can anti-cancer drugs be divided?

1. Cell cycle-specific drugs (active in specific phase of cell cycle)
2. Cell cycle-nonspecific drugs that kill both cycling and noncycling tumor cells

7

For metchlorethamine, and other drugs!! List class, mech, therapeutics, important side effects, other side effects, and miscellaneous

Class: Nitrogen mustard
Mech: alkylating agent that has spontaneous conversion to active metabolites in body fluids or enzymatically converted in liver
Thera: Hodgkin's; used topically for treatment of cutaneous T-cell lymphoma
Important SE's: none
Other SE's: severe nausea, vomiting, myelosuppression (leukopenia, thrombocytopenia)
Miscellaneous: not used much anymore due to sterility

8

For cyclophosphamide, list:

Class: Nitrogen mustard
Mech: alkylating agent; conversion hepatic cytochrome P450 to active metabolite phosphoramide mustard
Thera: Most widely used alkylating agent; singly or in combo for ALL, CLL, non-Hodgkin's, breast, lung and ovarian cancer
Important SE: Hemorrhagic cystitis (toxic metabolite acrolein accumulates) but hydrating and using MESNA can minimize problem
Other SE's: Nausea, vomiting, myelosuppression
Miscellaneous: relatively long plasma half-life (7-15 hours) and taken ORALLY!!

9

What is the only difference between ifosfamide (Ifex) and cyclophosphamide?

Sarcoma and testicular cancer for therapeutics

10

Carmustine (Gliadel) list

Class: nitrosourea
Mech: Alkylating agent
Therapeutics: brain tumors (cross BBB)
Important SE's: renal toxicity, pulmonary fibrosis
Other SE's: profound myelosuppression, severe nausea and vomiting

11

Lomustine (Ceenu) list

Class: nitrosourea
Mech: Alkylating agent
Therapeutics: brain tumors (cross BBB)
Important SE's: renal toxicity, pulmonary fibrosis
Other SE's: profound myelosuppression, severe nausea and vomiting

12

Decarbazine (DTIC)

Class: Triazene
Mech: Alkylating agent; prodrug activated by liver cytochromes
Thera: part of ABVD for Hodgkin's, also malignant melanoma
Other side effects: Nausea and vomiting, myelosuppression (neutropenia, thrombocytopenia), flu-like symptoms (fever, fatigue)
Miscellaneous: IV admin

13

Temozolomide

Class: Triazene
Mech: Alkylating agent, nonenzymatic conversion to methylhydrazine in physiologic pH
Thera: Malignant gliomas
Important side effects: None
Other side effects: same as DTIC
Miscellaneous: take orally

14

Cisplatin (Platinol)

Class: Platinum analogs
Mech: Alkylating agents that do not form carbonium ion intermediates or formally alkylate DNA; covalently bind nucleophilic sites on DNA (e.g., guanine N7); converted to active cytotoxic forms by reacting with water to form (+)charged, hydrated intermediates that react with DNA guanine, forming inter- and intrastand cross-links
Thera: Testicular, ovarian, cervical, and bladder cancers; also useful in treatment of head and neck cancer, and lung carcinoma
Important SE's: Nephrotoxicity, ototoxicity, peripheral motor and sensory neuropathy at high doses
Other SE's: Severe nausea and vomiting, mild to moderate myelosuppression

15

How is carboplatin (paraplatin) different from cisplatin?

Thera: Ovarian cancer
Important side effects: None
Other side effects: just myelosuppression

16

How is oxaliplatin (eloxatin) different from cisplatin and carboplatin?

Thera: gastric and colorectal cancer
Important SE's: peripheral sensory neuropathy (cold-incuded)
Other SE's: neutropenia

17

Procarbazine (Matulane)

Class: triazene
Mech: Alkylating agent (forms free radicals)
Thera: Hodgkin's lymphoma
Important SE's: May cause leukemia

18

What are alkylating agents for the most part?

Produce strong electrophiles through carbonium or ethyleneimonium ion intermediates, which covalently bond via alkylation of nucleophilic moieties in DNA (mostly N7 position of guanine); Cell Cycle Non-Specific (CCNS)

19

What are antimetabolites?

Structural analogs of folic acid or of the purine/pyramidine bases found in DNA; act in S-phase (cell cycle specific)

20

Methotrexate (Trexal)

Class: Folate analogs
Mech: Inhibits dihydrofolate reductase (DHFR), which converts dietary folate to tetrahydrofolate (THF) needed for thymidine and purine synthesis; given orally or intrathecally
Thera: Childhood ALL and choriocarcinoma; combination therapy for Burkitt's lymphoma and carcinomas of breast, ovary, head and neck, and bladder; administered intrathecally for meningeal leukemia and meningeal metastases of tumors (can't cross BBB); high-dose for osteosarcoma
Important SE's: Renal toxicity (crystallization in urine at high doses), hepatotoxicity (long-term, fibrosis/cirrhosis), reproductive (defective oogenesis or spermatogenesis, abortion)
Other SE's: Bone marrow (myelosuppression, spontaneous hemorrhage); GI toxicity (oral ulceration, stomatitis)
Miscellaneous: Can use leucovorin to prevent toxic effects of MTX, as healthy cells can take it up a lot better than tumor cells

21

Pemetrexed (Alimta)

Class: Folate analogs
Mech: Polyglutamate forms that inhibit THF-dependent enzymes (e.g., DHFR, TS); metabolized to polyglutamate forms that inhibit THF-dependent enzymes (e.g., DHFR, thymidylate synthase (TS))
Thera: Colon cancer, mesothelioma, non-small cell lung cancer, pancreatic cancer

22

5-fluorouracil (5-FU, Carac)

Class: Pyramidine analogs
Mech: 5-FU is converted to active metabolites: 5-FdUMP inhibits TS; 5-FdUTP incorporates into RNA & interferes with RNA function; prodrug ribosylated and phophosrylated into 5-FdUMP
Thera: Combination therapy for breast, colorectal, gastric, head and neck, cervical and pancreatic cancer; topically for basal cell carcinoma
Important SE's: Hand-foot syndrome (erythema, sensitivity of palms and soles), cardiac toxicity (acute chest pains)
Other SE's: Anorexia and nausea; mucosal ulcerations, stomatitis, diarrhea; thrombocytopenia and anemia
Misc: Leucovorin can potentiate effects of 5-FU; must be given IV (GI toxicity and rapid degradation + metabolism in gut and liver)

23

Cytarabine (AraC, Depocyt)

Class: Pyramidine analogs
Mech: Ara-C converted by deoxycytidine kinase to Ara-CMP --> Ara-CTP; terminates DNA synthesis as Ara-CTP
Thera: AML (most effective treatment), ALL and blast phase CML
Other SE's: Severe myelosuppression (leucopenia, thrombocytopenia, anemia), GI tract toxicity (ulceration, stomatitis, diarrhea)

24

Gemcitabine (dFdC, Gemzar)

Class: Pyramidine analogs
Mech: Converted to active metabolites: dFdCDP inhibits ribonucleotide reductase (lowers deoxyribonucleotide); dFdCTP incorporates into DNA, terminating DNA synthesis
Thera: Pancreatic cancer; effective against non-small cell lung cancer, ovarian, bladder, esophageal, and head and neck cancer
Other SE's: Myelosuppression (leucopenia, thrombocytopenia, anemia), flu-like
Misc: More effective against solid tumors than cytarabine

25

6-Mercaptopurine

Class: Purine analogs (antimetabolites)
Mech: Prodrug metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to 6-thioinosinic acid (TIMP); TIMP inhibits first step of de novo purine base synthesis and the formation of AMP and xanthinylic acid from inosinic acid, reducing purine levels. As well, TIMP is converted to thio-guanine ribonucleotides, inhibiting DNA and RNA synthesis
Thera: Maintain remission in acute ALL
Important SE's: Hepatotoxicity in prolonged use
Other SE's: Bone marrow suppression
Misc: Drug interaction with allopurinol (for gout), which inhibits xanthine oxidase; decrease 6-MP dose to avoid drug accumulation and toxicities

26

What are the 5 combo therapies? What drugs do they consist of?

1. ABVD (Doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine)
2. CHOP (Cyclophosphamide, hydroxydoxorubicin, vincristine (oncovine), prednisone)
3. MOPP (Mechlorethamine, vincristine (oncovine), procarbazine, prednisone)
4. CMF: Cyclophosphamide, methotrexate, 5-fluorouracil
5. FEC: 5-fluorouracil, epirubicin, cyclophosphamide

27

How are alkylating agents toxic? How is there resistance to alkylating agents?

1. Bone marrow toxicity (thrombo, anemia, neutropenia)
2. Mucosal toxicity (oral mucosal ulceration, intestinal denudation
3. Nausea and vomiting
4. Toxic effects on repro
5. Increased risk of leukemia (e.g. procarbazine);
1. Decreased perm/uptake of drugs
2. Increased metabolism rates of activated to inactive species
3. Enhanced activity of DNA repair pathways
4. Increased production of glutathione (inactivates alkylating agents)

28

Mech of MTX resistance?

1. Reduced drug uptake
2. Increased DHFR production (gene amplification)
3. Decreased affinity of DHFR for MTX

29

Mech of 6-MP resistance?

1. Reduced conversion o6-MP to TIMP because of decreased HGPRT
2. Decreased drug transport