Anti-Neoplastics Part II

Question 1

Mechlorethamine

Answer 1

Alkylating agent-nitrogen mustard, cell cycle non-specific, SE: nausea, vomiting, BM suppression mild alopecia. *Bifunctional, produces DNA cross links, highly reactive, disappears from blood stream in seconds to minutes, doesn’t enter CNS. For Hodgkins and Non-hodgkins.

Question 2

Cyclophosphamide

Answer 2

Alkylating agent-nitrogen mustard, cell cycle phase non-specific (doesn’t kill G0), SE: nausea, vomiting, limited BM suppression, alopecia. *Broad spectrum, most widely used in class, PRODRUG activated by P450s. Possible bladder toxicity, prevent with mesna.

Question 3

Carmustine

Answer 3

Alkylating agent-Nitrosourea, cycle-non specific (kills cells in G0). Can cross BBB, treats brain tumors. SE: nausea, vomiting, BM suppression, alopecia.

Question 4

Antimetabolites

Answer 4

Structural analogs of compounds required for intermediary metabolism, greatest effectivness in rapid proliferation, S-phase specific

Question 5

Methotrexate

Answer 5

Binds to dihydrofolate and prevents tetrahydrofolate formation. Blocks purine and pyrimidine synthesis. Use in acute lymphocytic leukemia, choriocarcinoma. SE: intestinal epithelial damage, BM suppression, renal tubular necrosis, displaces other drugs from serum albumin. *Followed by leucovorin rescue

Question 6

Leucovorin

Answer 6

Fully reduced folate that does not require reduction by DHFR. Normal cells have increased capacity to bring this into the cell. Use after high doses of Methotrexate.

Question 7

Fluorouracil (5-FU)

Answer 7

Pyrimidine analog, activated in cells to FUTP and FdUMP; nhibits RNA synthesis and DNA synthesis. Use for GI cancer. SE: Nausea, anorexia, diarrhea, BM suppression.

Question 8

Cytarabine (Ara-C)

Answer 8

Pyrimidine analog that competes for phosphorylation of cytidine, causes DNA chain termination. Use for acute leukemias. SE: BM suppression, neurotoxicity

Question 9

Mercaptopurine

Answer 9

Purine analog, converted in cells to ribonucleotide that inhibits RNA and DNA synthesis. Uses: acute leukemia. SE: BM depression, vomiting, nausea, anorexia, JAUNDICE. *TMPT polymorphisms require reduced doses to prevent serious bone marrow toxicity.

Question 10

Hydroxyurea

Answer 10

Inhibits ribonucleotide reductase (blocks conversion of ribonucleotides to dNTPs, preventing DNA synthesis), arrests cells at G1-S. Useful with radiation. Uses: granulocytic leukemia, SE: BM suppression, GI disturbances

Question 11

Vinca Alkaloids

Answer 11

From periwinkle plant. Vinblastine and Vincristine. Bind to tubulin, destabilize MT and mitotic spindle formation, arrest cells in M phase.

Question 12

Vinblastine

Answer 12

Inhibits MT and mitotic spindle formation. SE: Strong BM suppression (dose limiting), epithelial ulcerations. Uses: Lymphomas, breast cancer

Question 13

Vincristine

Answer 13

Inhibit MT and mitotic spindle formation. SE: less BM toxicity than Vinblastine, alopecia, peripheral neuropathy. Uses: acute lymphocytic leukemia, lymphoma, wilm’s tumor, neuroblastoma.

Question 14

Paclitaxel

Answer 14

Taxane-enhances assembly and stability of MTs by binding to B-subunit. Blocks in late G2. Uses: refractory ovarian cancer, breast cancer. *Interferes with DNA repair, intensifying effects of cisplatin and cyclophosphamide. SE: Dose-limiting leukemia, perpheral neuropathy, myalgia/arthralgia

Question 15

Doxorubicin

Answer 15

Antitumor antibiotic. Intercalates in DNA, distorting helix; causes lipid peroxidation and free radical formation; binds to DNA topoisomerase II. Cycle-specific, phase non-specific, most active in this class, wide spectrum. Uses: lymphomas, breast, ovary, small cell lung cancer *SE: dilated CARDIOMYOPATHY, BM depression, alopecia, GI problems

Question 16

Bleomycin

Answer 16

Prodrug. Iron-containing glycopeptides that bind to DNA. Causes oxidative damage and DNA strand breaks. Phase specific-G2. Uses: germ cell tumors, head, neck, lung, lymphomas. *SE: PULMONARY TOXICITY Minimal BM suppression, skin vesiculation, hyperpigmentation

Question 17

Etoposide (VP 16)

Answer 17

From mandrake plant. Irreversibly stabilizes DNA-topoisomerase II. dsDNA breaks cannot be repaired. Phase specific- G2. Uses: Lymphoma, acute leukemia, small cell lung, testes. SE: dose-limiting leukopenia, nausea, vomiting, diarrhea, alopecia.

Question 18

Biological Response Modifiers (BRM)

Answer 18

Naturally occuring proteins that mimic or impact natural proteins. Add potential benefit with less added toxicity. Variable responses, can be serious side effects.

Question 19

Filgrastim (G-CSF)

Answer 19

Granulocyte colony stimulating factor. Limits chemotherapy-induced neutropenia. Promotes progenitors, expands the absolute population of neutrophils for quicker recovery from BM suppression. SE: Bone pain

Question 20

Trastuzumab

Answer 20

Humanized monoclonal ab that binds to HER2 receptor. Used in breast cancers that overexpress HER2. SE: cardiomyopathy, hypersensitivity, infusion reactions.

Question 21

Cisplatin

Answer 21

Platinum coordination complex. Activated by hydrolysis, causes DNA cross links. Cycle-specific, phase non-specific. wide anti-tumor spectrum. Uses: advanced ovarian, testicular cancer, many others. SE: NEPHROTOXICITY, otoxicity, peripheral neuropathy, electrolyte disturbances, nausea, BM suppression.

Question 22

Procarbazine

Answer 22

Atypical alkylating agent. Activated in vivo to a methylating agent which causes chromosomal damage. No cross resistance with other alkylating agents. Uses: Hodgkin’s lymphoma. Greatest effect in G1 and S. SE: BM suppression, nausea, vomiting

Question 23

Hormone Therapy

Answer 23

Useful in steroid hormone dependent tumors. Breast cancers with estrogen and progesterone receptors respond best. Can use opposite steroidal hormone therapy or anti-hormonal compounds-these therapies decrease growth fraction and put more cells in G0. Responses can be dramatic and prolonged.

Question 24

Prednisone

Answer 24

Binds to steroid receptors, arrrests cells at G1. Depresses growth-related gene expression, induces nucleases for cell lysis. Uses: lymphoma, leukemia, breast cancer. Also an anti-emetic, stimulates appetite, anti-inflammatory. SE: immunosuppression, limited BM suppression, weight gain, fluid retention, psychological side effects

Question 25

Tamoxifen

Answer 25

Non-steroidal antiestrogen that competitively blocks estrogen receptors in breast tissue. Estrogen agonist in bone-prevents post-menopausal bone loss. Cytostatic, tumor returns when drug is stopped. Uses: breast cancer, breast cancer prophylaxis. *activated by CYP2D6-ultrafast metabolizers have more side effects. SE: nausea, fatigue, hot flashes, bone/muscle pain

Question 26

Letrozole

Answer 26

Blocks conversion of androgens to estrogens by inhibiting aromatase. Uses: 1st line tx of post-menopausal breast cancer. SE: DECREASED bone density, hot flashes, nausea, fatigue, bone/muscle pain

Question 27

Leuprolide

Answer 27

GnRH analog, stimulates LH and FSH release and testosterone surge-initial disease flare. After 2-4 weeks it desensitizes GnRH signaling and decreases LH and FSH to castration levels. Use: Advanced hormonally responsive prostate cancer SE: hot flashes, impotence, disease flare in 1st 2 weeks.

Question 28

Flutamide

Answer 28

Non-steroidal antiandrogen, blocks androgen receptors. Uses: Metastatic prostate cancer. SE: gynecomastia, diarrhea, hepatotoxicity

Question 29

Multi-Drug Resistance

Answer 29

Mediated by ATP-dependent drug efflux pumps. Can cause simultaneous resistance to many drugs. Prominent for vincristine, vinblastine, doxorubicin, bleomycin, etoposide, paclitaxel.

Question 30

Sequential Blockade

Answer 30

Simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway. Ex: hydroxyurea + cytarabine and methotrexate + 5 FU

Question 31

Concurrent Inhibition

Answer 31

Inhibitors block two separate pathways that lead to the same end product

Question 32

Complementary Inhibition

Answer 32

One drug affects the function of an end product, the other affects the synthesis of that end product. Ex: Cytarabine (inhibits DNA synthesis) + Doxorubicin (causes DNA damage)

Question 33

Rescue

Answer 33

“Rescues” the patients cells from treatment. Ex: leucovorin after methotrexate, or a bone marrow transplant after any BM suppressive drug

Question 34

Synchronization

Answer 34

Synchronize cells so they are in one phase, and then use a drug specific for that phase. Ex: 5 FU blocks cells in S phase, cytarabine kills cells in S phase (not very successful in vivo)

Question 35

Recruitment

Answer 35

Bringing cells out of G0 and into cell cycle. Ex: Therapy with cell cycle-non specific drugs (alkylating agents or nitrosoureas) and then hitting them with cell cycle specific drugs.