Oncology-Alkylating Agents

Oncology-Alkylating Agents

I. Introduction

Alkylating agents are antiproliferative cytotoxic drugs used in cancer chemotherapy. They function by covalently binding to DNA via alkyl groups, primarily causing cross-linking. This leads to cell cycle arrest (G1-S transition), followed by either DNA repair or apoptosis (programmed cell death).

II. Clinical Use

Alkylating agents are widely used to treat:

• Leukemia
• Lymphoma
• A range of solid tumors

III. Mechanisms of Resistance

Resistance to alkylating agents is complex and varies depending on the specific agent. Key mechanisms include:

• Enhanced DNA repair: Increased expression of enzymes like O6-alkyltransferase (especially relevant for nitrosoureas).
• Increased detoxification: Elevated levels of:
  • Glutathione
  • Metallothionein
  • Glutathione-S-transferase

IV. Examples of Alkylating Agents

This section details key characteristics, uses, and toxicities of specific alkylating agents. Pay close attention to the differences in their mechanisms, side effects, and clinical applications.

Agent	Description	Clinical Use	Key Toxicities	Notes
Melphalan	Nitrogen mustard derivative + phenylalanine (targets dividing cells via amino acid uptake)	Leukemia, lymphoma, solid tumors	Myelosuppression (bone marrow suppression)
Chlorambucil	Phenylbutyric acid derivative of nitrogen mustard (oral administration)	Solid and hematological malignancies	Myelosuppression	Well-absorbed orally
Cyclophosphamide	Extensively used; pro-drug activated by hepatic P450	Broad range of cancers	Marrow suppression, alopecia, nausea, vomiting	Relatively low non-hematological toxicity; used in high-dose regimens
Ifosfamide	Isomer of cyclophosphamide; metabolized to chloroacetaldehyde (toxic metabolite)	Broad range of cancers	Alopecia, hemorrhagic cystitis (mitigated by mesna)	Mesna co-administration is crucial to reduce hemorrhagic cystitis
Busulfan	Specific use in Chronic Myelogenous Leukemia (CML)	CML	Myelosuppression, hepatic veno-occlusive disease, hyperpigmentation, pulmonary fibrosis	Well absorbed from GI tract
Carmustine (BCNU)	Lipophilic molecule	CNS tumors, high-dose conditioning	Myelosuppression
Temozolomide	Newer agent	Glioma, melanoma

Important Note: Both cyclophosphamide and ifosfamide are pro-drugs activated by hepatic cytochrome P450 to form nitrogen mustards. Remember the differences in their toxicity profiles and how those toxicities are managed clinically.