Alkylating antineoplastics

Question 1

Alkylating agents

Answer 1

1. MOA: miscoding of DNA strands leading to strand breakage, incomplete repair of alkylated segment leading to strand breaks, excessive crosslinking of DNA and loss of strand separation at mitosis.
2. SE: vesicant (damage tissues at injection site), damages rapidly dividing cells ( GI, BM, sperm, hair), N/V, BM depression, sterility common, teratogenic.
3. Resistance: increased ability to repair DNA, decreased permeability to drug, increase glutathione.

Question 2

Mecholorethamine

Answer 2

1. MOA: phase non-specific but M and G1 most sensitive
2. SE: strong vesicant, hematologic toxicity, hyperuricemia (reduce with allopurinol and alkalinization of urine), renal failure (due to increased uric acid), teratogen

Question 3

Cylcophosphamide

Answer 3

1. MOA: prodrug activated by CYP450
2. Kinetics: intravenous (not a vesicant), oral
3. SE: Hematolgic toxicity, alopecia, HEMORRHAGIC CYSTITIS (on test, tx w/hydration, frequent urination, MESNA), SIADH
4. Use: broad spectrum- leukemias/lymphomas, Hodgkins disease, testicular cancer, breast, lung, ovarian, endometrial, cervical, immunosuppression.

Question 4

Ifosfamide

Answer 4

1. MOA: synthetic analogue of cyclophosphamide, similar mech. Must be activated by P450
2. SE: can cause hemorrhagic cystitis, admin w/MESNA
3. Use: activity better than cyclophosphamide: soft tissue sarcomas, osteogenic sarcomas, lung cancer, breast cancer.

Question 5

Chlorambucil

Answer 5

1. Used for chronic lymphocytic leukemia, plasma cell myeloma, AI disease

Question 6

Thiotepa

Answer 6

1. Ethylenimine derivative, not phase specific, admin IV/intracavitary/intravesicular/intrathecal
2. Use: carcinomas of breast, ovary, bladder

Question 7

Benadmustine

Answer 7

1. Newer, used for CLL and non-hodgkins lymphoma

Question 8

Busulfan

Answer 8

1. MOA: bifunctional alkylater
2. Kinetics: T1/2 of 2-3 min, oral
3. SE: few, mainly myelosuppression and hyperuricemia due to cell breakdown (use hydration and allopurinol)
4. Use: CML

Question 9

Carmustine (BCNU), Lomustine (CCNU), Streptozocin (Zanosar)

Answer 9

1. MOA: Nitrosureas, bifunctional alkylator, not phase specific, must be activated in vivo
2. Kinetics: highly lipid soluble (enter CNS), oral/IV
3. SE: BCNU and CCNU cause profound myelosuppression, streptozocin does not.
4. Use: Carmustine-Brain tumoors, hodgkins/non-hodgkins, multiple myelomas. Lomustine-Brain tumors, melanoma, GI cancer. Sterptozocin-selective for pancreatic B cells

Question 10

Dacarbazine

Answer 10

1. MOA: acitvated by P450, acts by DNA cross linking (kills cells in all phases)
2. Kinetics: IV admin, T1/2 18 min, given once every 28 days
3. Use: Hodgkins, metastatic/malignant melanoma, adult sarcomas. Temozolomide used for malignant glioma an astrocytoma (acts similar to dacarbazine). Procarbazine for hodgkins/non-hodgkins and brain tumors, one metabolite is an MAOI, may cause secondary cancers.

Question 11

Cisplatin, Carboplatin, Oxalaplatin

Answer 11

1. MOA: platinum coordination compounds, affects cells in all phases (esp. S phase), bifunctional alkylating agents, cause inter-intrastrand DNA crosslinking, disrupt DNA double helix, interferes w/ DNA syn, sensitize cells to cytotoxic effects of radiation and may improve response.
2. SE: renal dysfunction (tx w/hydration and amifostin), acoustic nerve damage (tinnitus).