Antibiotics for cancer, Microtubule agents

Question 1

Antibiotics as anticancer agents

Answer 1

1. MOA: intercalate and bind to DNA btw base pairs on adjacent strands, destroy DNA and inhibit RNA and DNA pol, no cell cycle specificity (best in S phase tho)
2. Resistance: due to diminished drug uptake by tumor cells or P glycoprotein pumping drug out
3. Admin: doxorubicin/daunorubicin/idarubicin given IV. Valrubicin instilled in bladder.
4. Kinetics; long t1/2, metabolized by liver

Question 2

Doxorubicin

Answer 2

1. Use: lymphoma/leukemia/hodgkins, solid tumors, sarcomas, thyroid carcinoma
2. SE: iron exacerbates generation of free radicals leading to cardiotoxicity, red urine
3. Other: dexrazoxane is used in women treated w/doxorubicin for breast cancer to chelate iron and decrease likelihood of cardiomyopathy.

Question 3

Daunorubicin

Answer 3

1. Used in acute non-lymphoblastic leukemia and in ALL

Question 4

Idarubicin and MItoxantrone

Answer 4

1. with cytarabine in AML
2. Less cardiotoxic than others
3. Mitoxantrone used for various leukemias, hodgkins, prostate cancer

Question 5

Bleomycin sulfate

Answer 5

1. MOA: group of glycoproteins, causes chain breaks and fragmentation, cell cycle specific for late G2 and early M phase.
2. SE: little myelosuppression, pulmonary fibrosis, cutaneous toxicity (rash/hyperpigment/thickening of skin), arteritis of extremeties similar to Raynauds, may exacerbate RA
3. Use: advacned testicular carcinoma, ovarian cancer, squamous cell carcinoma, hodgkins/non-hodgkins

Question 6

Dactinomycin

Answer 6

1. MOA: binds dsDAN, blocks RNA syn, stops DNA transcription, inhibts rapidly proliferating cells.
2. SE: N/V, myelosuppression, radiation recall rxns, mucositis/Diarrhea/alopecia
3. Use: wilms tumor, rhabdomyosarcoma, advanced choriocarcinoma, sarcomas

Question 7

Mitomycin

Answer 7

1. MOA: cell cycle non specific, alkylates and cross links DNA. Must be metabolized by hepatic microsomal enzymes to be active.
2. SE: severe, delayed myelosuppression
3. Use: stomach, pancreatic, breast, colon, head neck and lung cancers, especially good for adenocarcinomas of GI

Question 8

Microtubule Inhibitors

Answer 8

1. MOA: bind to tubulin, disrupt mitotic spindle apparatus, prevent segregation of chromosomes lined up in metaphase-metaphase arrest, specific for M phase
2. Kinetics: resistance due to increased levels of P glycoprotein, does not get into brain, metabolized by liver

Question 9

Vincristine

Answer 9

Microtubule inhibitor

Hodkins, childrens leukemia, non-hodkins, pediatric solid tumors, adult tumors of lung/breast/cervix/bladder

SE: neurotoxic, peripheral neuropathy, lost of DTRs, paresthesias, constipation, alopecia, little myelosuppression

Question 10

Vinblastine

Answer 10

Microtubule inhibitor

Testicular carcinoma (w/ bleomycin and cisplatin), hodgkins, kaposi sarcoma

SE: less neurotoxic than vincristine, bone marrow depression

Question 11

Vinorelbine

Answer 11

Microtubule inhibitor

Advanced non-small cell lung cancer, breast cancer

SE: less neurotoxic, some myelosuppression

Question 12

Paclitaxel

Answer 12

1. MOA: binds to tubulin and microtubulin, arrests mitosis, stabilizes microtubules and inhibits disassembly, disurpts axonal transport in nerve fibers
2. Kinetics: active in G2 and M phase, resistance due to increased transport out of cells, metabolized by liver
3. SE: Myelosuppression, alopecia, peripheral neuropathy, myalgias/athralgias, severe hypersensitivity, CV (mild hypotension and bradycardia)
4. Use: breast/ovary carcinoma, kaposi

Question 13

Docetaxel

Answer 13

Similar to paclitaxel, more toxic (edema and skin lesions)

Question 14

Ixabepilone

Answer 14

Microtubule stabilizer, used in resistant breast cancer, may cause liver toxicity