B-34. Cancer chemotherapy - alkylating agents.

Question 1

Classical Alkylating Agents

Answer 1

• mustard nitrogen derivatives.

1. Cyclophosphamide
2. Ifosfamide
3. Mechlorethamine

Question 2

Cyclophosphamide (MOA, resistance, kinetics, SE, indications)

Answer 2

1. MOA: prodrug metabolized by CYP450 → alkylates guanine bases → inter-/intrastrand cross-links
2. Resistance: increased glutathione via ↑ glutathione S-transferase conjugates CP; aldehyde dehydrogenase inactivates CP
   * can ↑ efficacy by co-admin of disulfiram (aldehyde DH inhibitor)
3. Kinetics: parenteral admin
4. Side Effects:
   a. Pulmonary fibrosis
   b. Hemorrhagic cystitis - in about 10%; via metabolite acrolein; co-admin with NAC or mesna
   * CP increases risk of high-grade transitional cell carcinoma + other bladder cancer
   c. SIADH - may induce hyponatremia
   d. Gonadotoxicity - both ovaries + testes; may → infertility / premature menopause
5. Indications:
   a. Solid tumors - breast cc. (combo with 5-FU) and ovarian cc.
   b. Childhood tumors - Wilms tumor, rhabdomyosarcoma, etc.
   c. Leukemia and lymphomas
   d. RA - not first-line (MTX first, then others, then CP)

Question 3

Ifosfamide

Answer 3

similar to CP.

can cause encephalopathy and hemorrhagic cystitis (always given with mesna).

Question 4

Mechlorethamine

Answer 4

prototype alkylating agent, no longer used.

now scheduled as a chemical weapon.

Question 5

Platinum analogs (drugs, MOA, indications)

Answer 5

1. Drugs:
   a. Cisplatin
   b. Carboplatin
   c. Oxaliplatin
2. MOA: Platinum binds guanine (on N7) + forms inter-/intrastrand cross-links → ↓ DNA synth / function.
3. Indications: mainly solid tumors … NSCLC, SCLC, testicular, ovarian + bladder cc.
   * Mainly differ in the severity of their side effects, detailed below.

Question 6

Cisplatin

Answer 6

1. Nephrotoxic - including ATN and vasoconstriction; prevent w/ hydration, mannitol, NAC
   * treat with amifostine, a thiophosphate that binds toxic free radical metabolites
2. Neurotoxic - symmetrical peripheral neuropathy (stocking / glove dist.)
3. Ototoxicity - worst of -platins; affects outer hair cells → dose-dep. high frequency loss / tinnitus

Question 7

Carboplatin

Answer 7

1. Less oto-/nephrotoxic; only high doses cause neurotoxicity!
2. Dose-limiting myelosuppression (worst -platin for bone marrow!)

Question 8

Oxaliplatin

Answer 8

1. Indications: specifically colorectal cancer, as well as other -platin solid tumor indications
2. Ototoxicity / nephrotoxicity is rare, but can still cause peripheral neurotoxicity

Question 9

Nitrosoureas (Drugs, MOA, indications, SE)

Answer 9

1. Drugs: Lomustine and Carmustine
2. MOA: highly lipophilic after non-enzymatic hydroxylation in liver → cross BBB and alkylate DNA.
3. Indications: brain tumors such as glioblastoma multiforme.
4. Side Effects: CNS neurotoxicity → convulsions, dizziness, ataxia.

Question 10

Others alkylating agents

Answer 10

1. Busulfan

a. MOA: forms intrastrand cross-links → prevents replication + causes apoptosis
b. Indications: used for BM ablation before BM transplant
c. Side Effects:
* Pulmonary effects - pulmonary fibrosis, acute lung injury and alveolar hemorrhage
* Hyperpigmentation - so-called “busulfan tan”

2. (Procarbazine - given orally for brain tumors and lymphomas; can cause CNS toxicity).
3. (Dacarbazine - given parenterally in melanoma and Hodgkin lymphoma; not used much anymore).