What is the classification, mechanism of action, metabolism, and toxicity management of chemotherapy agents, including alkylating agents, antimetabolites, and topoisomerase inhibitors?

From the Guidelines

Chemotherapy agents can be broadly classified into several categories, including alkylating agents, antimetabolites, topoisomerase inhibitors, and antimicrotubule agents, each with distinct mechanisms of action, metabolism, and toxicity profiles. The classification and management of these agents are crucial for optimizing treatment outcomes and minimizing adverse effects. According to the most recent guidelines, including the NCCN clinical practice guidelines in oncology 1, chemotherapy agents are categorized into "preferred," "other recommended," and "useful in certain circumstances" based on their efficacy, toxicity, and patient-specific factors.

Mechanisms of Action and Metabolism

• Alkylating agents, such as cyclophosphamide, cisplatin, and carboplatin, work by adding alkyl groups to DNA, causing cross-linking that prevents cell division. They undergo hepatic metabolism and can cause myelosuppression, nausea, and nephrotoxicity.
• Antimetabolites, such as methotrexate, 5-fluorouracil, and gemcitabine, interfere with DNA and RNA synthesis by mimicking natural metabolites. They can cause mucositis, myelosuppression, and hepatotoxicity, managed with leucovorin rescue for methotrexate toxicity.
• Topoisomerase inhibitors, like etoposide, irinotecan, and doxorubicin, prevent DNA unwinding and repair, leading to cell death. They can cause myelosuppression and, in the case of anthracyclines like doxorubicin, cardiotoxicity, which is managed by limiting cumulative doses and using dexrazoxane.
• Antimicrotubule agents, such as paclitaxel, docetaxel, and vincristine, disrupt microtubule function, preventing mitosis. They can cause peripheral neuropathy, myelosuppression, and hypersensitivity reactions, requiring premedication with steroids and antihistamines.

Toxicity Management

• Proper dosing, monitoring, supportive care, and prophylactic medications are crucial for managing chemotherapy toxicities and improving patient outcomes. This includes hydration and antiemetics for alkylating agents, leucovorin rescue for methotrexate toxicity, and limiting cumulative doses of anthracyclines to prevent cardiotoxicity.
• The NCCN guidelines recommend individualized treatment decisions based on previous therapies, pre-existing comorbidities, nature of the disease, toxicity profiles, patient preferences, and access to agents 1.
• A recent study on the toxicity of immunotherapy combinations with chemotherapy highlights the importance of collaborating with organ specialists and toxicity experts to identify the culprit drug and manage toxicities effectively 1.

Key Recommendations

• The NCCN panel recommends preferred single agents, including taxanes (paclitaxel), anthracyclines (doxorubicin and liposomal doxorubicin), antimetabolites (capecitabine and gemcitabine), microtubule inhibitors (eribulin and vinorelbine), and platinum agents for patients with triple-negative tumors and germline BRCA1/2 mutations 1.
• Eribulin, a nontaxane microtubule inhibitor, is recommended for patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease 1.

From the FDA Drug Label

The mechanism of action is thought to involve cross-linking of tumor cell DNA. Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. Doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and left ventricular ejection fraction.

Classification and Mechanism of Action:

• Doxorubicin is an anthracycline antibiotic that works by intercalating DNA strands, thereby preventing their replication.
• Cyclophosphamide is an alkylating agent that cross-links tumor cell DNA, interfering with the growth of susceptible rapidly proliferating malignant cells.

Metabolism:

• Cyclophosphamide is activated in the liver by hepatic microsomal cytochrome P450s to form 4-hydroxycyclophosphamide.
• Doxorubicin is metabolized to doxorubicinol, which has 5% of the cytotoxic activity of doxorubicin.

Toxicity Management:

• Monitoring of complete blood counts, hepatic function tests, and left ventricular ejection fraction is required for doxorubicin.
• Patients with severe renal impairment should be closely monitored for toxicity when receiving cyclophosphamide 2.
• The use of cardioprotectants like dexrazoxane may be considered to minimize the risk of cardiotoxicity associated with doxorubicin 3.

From the Research

Classification of Chemotherapy

• Alkylating agents: work by adding an alkyl group to the DNA of cancer cells, interfering with their replication and ultimately leading to cell death 4, 5, 6
• Antimetabolites: interfere with the normal metabolic processes of cells, preventing cancer cells from growing and multiplying 4, 7
• Topoisomerase inhibitors: target the enzyme topoisomerase, which is necessary for DNA replication, thereby preventing cancer cells from dividing 7
• Anthracycline antibiotics: work by intercalating into DNA and disrupting the replication process, ultimately leading to cell death 4, 8
• Plant alkaloids: work by inhibiting microtubule formation, preventing cancer cells from dividing 4

Mechanisms of Action

• Alkylating agents: cyclophosphamide has immunosuppressive and immunomodulatory properties, and can selectively suppress regulatory T cells (Tregs) 5
• Antimetabolites: methotrexate has a high-binding affinity for certain molecular targets, and can modulate the Wnt and Hh pathways 7
• Topoisomerase inhibitors: can cause DNA damage and prevent cancer cells from dividing 7
• Anthracycline antibiotics: can cause cardiotoxicity, including cardiac events such as myocarditis, pericarditis, and congestive heart failure 8

Metabolism

• Cyclophosphamide is metabolized in the liver and has a half-life of several hours 5
• Methotrexate is metabolized in the liver and has a half-life of several hours 7
• Other chemotherapeutic agents have varying metabolism and half-lives, depending on the specific agent and individual patient factors 4, 8, 6

Toxicity Management

• Cardiotoxicity: can be managed with cardioprotective agents such as dexrazoxane, and by monitoring cardiac function and adjusting chemotherapy doses as needed 8
• Myelosuppression: can be managed with growth factor support and transfusions as needed 4, 5
• Nausea and vomiting: can be managed with antiemetic medications and other supportive care measures 4, 7
• Other toxicities: can be managed with supportive care measures and adjusting chemotherapy doses as needed, depending on the specific agent and individual patient factors 4, 7, 5, 8, 6