Alkylating agents

Mechanism and Class Overview

• Class mechanism: Form covalent adducts and cross-links with DNA (classically at the N-7 of guanine), blocking DNA synthesis and transcription; cell-cycle independent (act on dividing and resting cells).
• Resistance: ↑ aldehyde dehydrogenase, ↓ P450 activation, ↑ DNA repair, and ↑ intracellular sulfhydryl (thiol) content.
• Secondary malignancy: A defining class toxicity. Alkylators (especially melphalan, procarbazine, cyclophosphamide, and the nitrosoureas) carry a dose- and duration-related risk of treatment-related MDS/AML, typically 5 to 7 years after exposure.

Nitrogen Mustards

Cyclophosphamide (Cytoxan)

• Mechanism: Requires multistep hepatic P450 activation; the final metabolites cross-link DNA. Resistance from ↑ aldehyde dehydrogenase and ↓ P450.
• Pharmacokinetics: Good oral absorption; dose reduce with ↓ CrCl; interacts with warfarin. Low albumin is associated with ↑ toxicity.
• Hemorrhagic cystitis: Occurs in 5 to 10% from accumulation of the metabolite acrolein in the bladder; can lead to bladder scarring and bladder cancer. Prevented with MESNA, whose sulfhydryl group detoxifies acrolein. MESNA is dosed off the parent drug dose (oral dose is twice the IV dose, bioavailability ~50%; the oral form tastes very bad) and protects the bladder only, not against the other toxicities.
• Toxicities: Myelosuppression, SIADH, nephrotoxicity, hemorrhagic cystitis, secondary AML, cardiotoxicity (high-dose), immunosuppression, alopecia, sterility.

Ifosfamide (Ifex)

• Mechanism: Oxazaphosphorine structurally similar to cyclophosphamide; same mechanism and shares myelosuppression, SIADH, nephrotoxicity, and hemorrhagic cystitis (prevent with MESNA).
• Neurotoxicity: Distinctive; from accumulation of chloroacetaldehyde (confusion, somnolence, lethargy progressing to delirium, psychosis, then seizure/status or coma). Treat grade III to IV with methylene blue or thiamine. Chloroacetaldehyde forms via hepatic CYP3A4/CYP2B6; renal CYP3A5 may contribute to local proximal tubular toxicity.

Bendamustine (Treanda)

• Mechanism: Nitrogen mustard plus purine-analog hybrid.
• Indications: CLL, B-cell (indolent) lymphoma.
• Toxicities: Myelosuppression (onset 3 to 4 weeks after treatment), edema, fever, LFT elevation, infusion reactions. Hepatic elimination: do not use if AST/ALT 2.5 to 10x ULN with t-bili 1.5 to 3x ULN, t-bili > 3x ULN, or CrCl < 30.

Chlorambucil (Leukeran)

• Mechanism: Nitrogen mustard; slow-acting oral agent.
• Indications: CLL, indolent lymphoma, Waldenstrom.
• Toxicities: Myelosuppression, secondary malignancies (↑ risk with prolonged use).

Melphalan (Alkeran)

• Mechanism: Nitrogen mustard that forms carbonium ions and DNA cross-links; acts on rapidly dividing and resting cells.
• Indications: Multiple myeloma (including high-dose conditioning before autologous HSCT).
• Toxicities: Delayed myelosuppression (~3 to 4 weeks), esophagitis/mucositis (mnemonic: melphalan = mucositis), diarrhea, pulmonary fibrosis, secondary malignancies. Dose reduce in renal impairment.

Platinum Compounds

• Class mechanism: Bind DNA at the N-7 of guanine and adenine and produce cross-links, ↓ DNA synthesis and transcription. Resistance from ↑ intracellular sulfur, ↑ DNA repair, and ↓ MMR (except oxaliplatin, which works against MMR-deficient tumors).
• Elimination and interactions: All platinums are renally excreted (cisplatin ~90%) with minimal hepatic elimination, so no hepatic dose adjustment is needed. Cisplatin before paclitaxel reduces paclitaxel clearance (give paclitaxel first); not a universal platinum or taxane effect (docetaxel clearance largely unaffected); by convention, give paclitaxel before the platinum (carboplatin included).

Cisplatin (Platinol)

• Toxicities: Nephrotoxicity (assess renal function by CrCl/GFR (Cr > 1.5 or BUN > 25 are the label's retreatment-hold criteria, not a general contraindication); hydrate, use mannitol/saline, avoid other nephrotoxins), irreversible high-frequency ototoxicity (get a baseline audiogram; worse with loop diuretics), cumulative sensory peripheral neuropathy, often persistent or irreversible and may progress after discontinuation (coasting), highly emetogenic with delayed nausea on days 3 to 5, and ↓ Mg/Ca/K. ↓ elimination of etoposide, ifosfamide, MTX, and bleomycin; cisplatin LOWERS phenytoin levels (subtherapeutic, monitor and adjust).
• Cisplatin ineligibility (urothelial): ECOG PS ≥ 2 (or KPS 60 to 70), CrCl < 60, neuropathy grade ≥ 2, NYHA class ≥ III, or hearing loss grade ≥ 2.

Carboplatin (Paraplatin)

• Dosing: By AUC (usually 4 to 6) using the Calvert formula, AUC × (GFR + 25).
• Toxicities: Mainly myelosuppression (especially thrombocytopenia), highly emetogenic at AUC ≥ 4 per NCCN (ASCO: moderate, but NK1 triplet at AUC ≥ 4; MASCC/ESMO: AUC ≥ 5); far less nephrotoxicity/ototoxicity/neuropathy than cisplatin. Hypersensitivity typically emerges around the 7th to 8th dose (desensitize; skin testing can predict).

Oxaliplatin (Eloxatin)

• Toxicities: Chronic cumulative sensory neuropathy (worsens with each dose; recovery often slow over many months to years and may be incomplete) plus acute cold-triggered neurotoxicity (laryngeal dysesthesia: discomfort swallowing cold items, throat tightness, muscle cramps, usually self-limited). Myelosuppression, LFT elevation. Few drug interactions (unlike cisplatin). Reduce to 65 mg/m2 if CrCl < 30. For persistent grade 2 neuropathy consider dose reduction; for persistent grade 3 to 4 neuropathy discontinue oxaliplatin.

Nitrosoureas

Carmustine (BCNU) and Lomustine (CCNU)

• Mechanism: DNA alkylation and cross-linking; lipophilic and cross the blood-brain barrier, so used for CNS tumors.
• Indications: Glioblastoma, CNS lymphoma, melanoma.
• Toxicities: Delayed cumulative myelosuppression (space dosing ~q6wk), pulmonary toxicity (baseline DLCO and FVC), interstitial nephritis (check UA), and secondary malignancies.

Methylating and Triazene Agents

Temozolomide (Temodar)

• Mechanism: DNA methylation (prodrug converted to MTIC).
• Indications: Anaplastic astrocytoma and glioblastoma; melanoma.
• Pharmacokinetics: Good oral bioavailability with CNS penetration.
• Toxicities: Myelosuppression, prominent nausea/vomiting, fatigue, myalgias, constipation, headache/seizure, LFT elevation, photosensitivity, and PJP pneumonia (give TMP-SMX prophylaxis, especially with concurrent radiotherapy).

Dacarbazine (DTIC)

• Mechanism: P450 converts it to the active alkylator MTIC, causing DNA methylation, double-strand breaks, and apoptosis.
• Indications: Melanoma, Hodgkin lymphoma (ABVD).
• Toxicities: Highly emetogenic, delayed myelosuppression (~3 to 4 weeks), photosensitivity, myalgias, and injection-site pain.

Procarbazine (Matulane)

• Mechanism: ↓ transmethylation of methionine into t-RNA, ↓ DNA and RNA synthesis.
• Indications: Hodgkin lymphoma (MOPP, BEACOPP).
• Drug and food interactions: Weak MAO-inhibitor effect, so avoid tyramine-containing foods (risk of hypertensive crisis); also avoid sympathomimetics and tricyclic antidepressants, plus a disulfiram-like reaction with alcohol. Dose adjust with LFT elevation.
• Toxicities: Delayed myelosuppression (3 to 4 weeks), mood changes, infertility (azoospermia, ovarian failure), and secondary malignancies/AML.

Other Alkylating Agents

Busulfan (Busulfex)

• Mechanism: Reacts with the N-7 of guanosine to cross-link DNA; highly toxic to myeloid stem cells.
• Indications: HSCT conditioning; historically CML, ET, PV.
• Toxicities: Hepatic veno-occlusive disease (watch weight, ascites, hepatomegaly, bilirubin), mucositis, seizures (give antiseizure prophylaxis such as levetiracetam or phenytoin), and pulmonary fibrosis (onset 4 months to 10 years). Acetaminophen, metronidazole, and itraconazole (not fluconazole) ↑ busulfan levels; phenytoin ↓ levels.

Thiotepa

• Mechanism: Aziridine alkylating agent.
• Indications: Intravesical bladder cancer, HSCT conditioning (CNS penetration).
• Toxicities: Myelosuppression, CNS toxicity.