In-Depth Overview of 5 Anticancer Chemotherapy Drugs: From Mechanisms to Adverse Effects

Chemotherapy remains one of the cornerstone approaches in cancer treatment. Among the various classes of chemotherapeutic agents, alkylating agents are widely used in clinical practice due to their ability to directly damage tumor cell DNA and inhibit cell proliferation. DengyueMed provides a comprehensive introduction to five commonly used anticancer chemotherapy drugs—cyclophosphamide, ifosfamide, melphalan, chlorambucil, and busulfan—covering their pharmacological characteristics, mechanisms of action, clinical applications, and adverse reactions, to serve as a reference for clinical use.

Cyclophosphamide: One of the Most Widely Used Alkylating Agents

Cyclophosphamide (CTX) is a representative nitrogen mustard alkylating agent and one of the most extensively used drugs in clinical oncology. It is characterized by a broad antitumor spectrum, well-established efficacy, and relatively low cost.

Cyclophosphamide is a prodrug that becomes activated by hepatic enzymes after administration, producing cytotoxic metabolites such as phosphoramide mustard. These active compounds form DNA cross-links in tumor cells, disrupting DNA structure and function, inhibiting DNA replication and cell division, and ultimately inducing apoptosis.

Clinically, cyclophosphamide can be used alone or in combination with other chemotherapeutic agents. Its antitumor spectrum includes a wide range of malignancies, such as malignant lymphomas (Hodgkin and non-Hodgkin lymphoma), breast cancer, ovarian cancer, lung cancer, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. In addition, cyclophosphamide is also widely used in the treatment of autoimmune diseases, including systemic lupus erythematosus.

The most common adverse effect of cyclophosphamide is bone marrow suppression, typically manifesting as leukopenia and thrombocytopenia, which usually occur 1–2 weeks after treatment and gradually recover after drug discontinuation. Gastrointestinal reactions such as nausea, vomiting, and anorexia are also common and can be alleviated with appropriate premedication. Other potential adverse effects include alopecia, hemorrhagic cystitis, and hepatic or renal dysfunction. Hemorrhagic cystitis can be effectively prevented through adequate hydration and the use of mesna.

Ifosfamide: A Cyclophosphamide Derivative with a More Targeted Antitumor Spectrum

Ifosfamide (IFO) is a structural isomer of cyclophosphamide and belongs to the same class of nitrogen mustard alkylating agents. Although its mechanism of action is similar to that of cyclophosphamide, subtle differences in chemical structure result in variations in antitumor spectrum and toxicity profiles.

Ifosfamide requires metabolic activation in the liver to exert its antitumor effects. Its active metabolites bind to tumor cell DNA, interfere with DNA replication, and inhibit tumor growth.

Compared with cyclophosphamide, ifosfamide retains activity against certain drug-resistant tumor cells and demonstrates a stronger effect against solid tumors. Clinically, it is primarily used in the treatment of soft tissue sarcomas (such as rhabdomyosarcoma and synovial sarcoma), lung cancer, ovarian cancer, cervical cancer, and esophageal cancer. It is also used in hematologic malignancies such as lymphomas and leukemias, often in combination with agents like cisplatin and etoposide to enhance therapeutic efficacy.

The adverse effects of ifosfamide are generally similar to those of cyclophosphamide but exhibit some distinct features. Bone marrow suppression remains the primary toxicity, while gastrointestinal reactions such as nausea and vomiting are relatively common and may be more severe. Hemorrhagic cystitis, which occurs more frequently than with cyclophosphamide, is a characteristic adverse effect and requires concurrent administration of mesna and adequate hydration for prevention. In addition, neurotoxicity (e.g., somnolence, mental status changes, peripheral neuropathy), alopecia, and hepatic or renal dysfunction may also occur.

Melphalan: An Alkylating Agent Primarily Used in Hematologic Malignancies

Melphalan (L-PAM), also known as Alkeran, is an orally administered nitrogen mustard alkylating agent with good lipid solubility. It is rapidly absorbed after oral administration and widely distributed throughout the body, with relatively high concentrations in the bone marrow, liver, and kidneys.

Melphalan exerts its antitumor activity by alkylating DNA and inducing double-strand breaks, thereby inhibiting cell division. It is a cell cycle–nonspecific agent, exerting cytotoxic effects on both proliferating and resting tumor cells.

Clinically, melphalan is primarily used in hematologic malignancies and is a cornerstone therapy for multiple myeloma, where it can be administered alone or in combination with prednisone, significantly improving patient survival. It is also used in chronic lymphocytic leukemia, malignant lymphoma, and ovarian cancer. In addition, melphalan is widely employed as a conditioning agent prior to hematopoietic stem cell transplantation to eliminate residual malignant cells.

Bone marrow suppression is the most significant adverse effect of melphalan and is dose-dependent. Severe cases may result in pancytopenia, necessitating regular monitoring of blood counts. Gastrointestinal toxicity is generally mild, presenting as low-grade nausea, vomiting, or diarrhea, and is usually reversible upon discontinuation. Long-term use may cause alopecia, skin hyperpigmentation, and hepatic or renal impairment, while hypersensitivity reactions occur in rare cases.

Chlorambucil: A Mild-Acting Oral Chemotherapy Agent

Chlorambucil (CB1348) is an orally administered nitrogen mustard alkylating agent. Its mechanism of action is similar to that of other alkylating agents, involving DNA binding and disruption of DNA replication and transcription, thereby inhibiting tumor cell proliferation.

Chlorambucil is characterized by a milder cytotoxic profile and slower onset of action, with activity against both proliferating and resting cells. Due to its relatively low toxicity and good tolerability, it is particularly suitable for long-term treatment.

Clinically, chlorambucil is widely used as a first-line oral chemotherapeutic agent for chronic lymphocytic leukemia, effectively controlling disease progression and alleviating symptoms. It is also indicated for low-grade non-Hodgkin lymphoma (such as follicular lymphoma), ovarian cancer, and breast cancer, as well as certain autoimmune diseases, including rheumatoid arthritis. Owing to its favorable tolerability, it is often preferred for elderly patients or those with poor physical condition.

Adverse effects of chlorambucil are generally mild. Bone marrow suppression is the most common toxicity, usually presenting as mild to moderate leukopenia or thrombocytopenia with relatively rapid recovery. Gastrointestinal reactions are uncommon and typically limited to mild nausea or abdominal discomfort. Long-term use may result in alopecia, pruritus, mild hepatic or renal impairment, and, in rare cases, reproductive toxicity such as reduced sperm count or menstrual irregularities.

Busulfan: A Selective Agent for Chronic Myeloid Leukemia

Busulfan (BUS), also known as Myleran, is a bifunctional alkylating agent. Its mechanism of action involves binding to guanine residues in tumor cell DNA, forming cross-links that disrupt DNA structure and inhibit cell replication and division.

Busulfan exhibits high selectivity for the granulocytic lineage, with relatively weaker effects on lymphocytes. As a result, it is primarily effective against malignancies characterized by abnormal granulocyte proliferation.

Clinically, busulfan is mainly used in the treatment of chronic myeloid leukemia (CML) in the chronic phase. It is a classic therapeutic agent for CML, capable of significantly reducing leukocyte counts, alleviating splenomegaly, and controlling disease progression. Busulfan is also widely used as a conditioning agent prior to hematopoietic stem cell transplantation, particularly in patients with CML, to eradicate abnormal myeloid clones.

Bone marrow suppression is the principal adverse effect of busulfan and may be prolonged, potentially leading to severe cytopenias or even aplastic anemia. Close monitoring of blood counts and timely dose adjustment are essential. Long-term or high-dose use may result in pulmonary fibrosis, one of the most serious delayed toxicities, presenting with cough, chest tightness, and dyspnea, and requiring immediate discontinuation and symptomatic treatment. Other adverse effects include mild gastrointestinal symptoms, alopecia, skin hyperpigmentation, and hepatic or renal dysfunction.

Conclusion

Cyclophosphamide, ifosfamide, melphalan, chlorambucil, and busulfan are all alkylating agents used in cancer chemotherapy. Although they share similar mechanisms of action, they differ in antitumor spectrum, routes of administration, and toxicity profiles. Cyclophosphamide has the broadest clinical application; ifosfamide is particularly effective against solid tumors but carries a higher risk of hemorrhagic cystitis; melphalan remains a cornerstone therapy for multiple myeloma; chlorambucil offers mild action and good tolerability, especially for elderly or frail patients; and busulfan demonstrates high specificity for chronic myeloid leukemia but requires vigilance for long-term toxicities such as pulmonary fibrosis.

It is important to note that all chemotherapeutic agents carry inherent toxicity and exhibit interindividual variability. Clinical use should strictly follow medical guidance, with individualized treatment regimens based on tumor type, disease stage, and patient condition. Careful monitoring and proactive management of adverse reactions are essential to maximize therapeutic efficacy while minimizing patient burden.