Antineoplastic agents, also known as anticancer drugs or antineoplastic drugs, are medications used to treat malignant tumors. These drugs work through various mechanisms to kill or inhibit cancer cells to achieve the goal of treating malignant tumors. Based on their pharmacological actions, antineoplastic drugs can be divided into cytotoxic drugs and non-cytotoxic drugs, with the former primarily consisting of DNA-toxic drugs and the latter mainly comprising molecularly targeted antineoplastic drugs. Commonly used antineoplastic drugs include cisplatin, doxorubicin, paclitaxel, and imatinib.
Traditional cytotoxic drugs, due to their lack of sufficient selectivity for cancer cells, cause varying degrees of damage to normal tissue cells while targeting cancer cells. However, with advancements in tumor molecular biology and translational medicine, antineoplastic drugs have evolved from traditional cytotoxic drugs to non-cytotoxic drugs. Non-cytotoxic drugs are characterized by high selectivity and a high therapeutic index, offering significant clinical advantages.
Uses Antineoplastic drugs are primarily used in medical settings to treat cancer. Because some antineoplastic drugs also exhibit antiviral activity, they are used to treat certain viral infectious diseases. Certain steroid hormone drugs (used in endocrine therapy), although lacking direct antineoplastic activity, can regulate hormonal balance in the body and suppress certain functional adenocarcinomas, making them commonly used in combination therapies with antineoplastic drugs. Additionally, antineoplastic drugs are employed in scientific research to further understand the molecular biology of cancer through studies of their pharmacological effects.
History
The first antineoplastic drug, nitrogen mustard, was developed in the 1940s by Louis S. Goodman and Alfred Gilman, Sr. through chemical modification of mustard gas (chemically known as dichlorodiethyl sulfide). Subsequently, chlormethine hydrochloride was approved for clinical use in 1949 as the first antineoplastic drug for treating lymphoma and Hodgkin lymphoma. The first aromatic nitrogen mustard drug, chlorambucil, was approved in 1957 for treating chronic lymphocytic leukemia.
Early antineoplastic drugs were mostly identified through random screening using animal transplantable tumors. Tumor cells exhibit higher phosphoramidase activity than normal cells, and the phosphoryl group, as an electron-withdrawing group, reduces the electron cloud density on the nitrogen atom in nitrogen mustards. Based on this principle, H. Arnold synthesized cyclophosphamide in 1957, which achieved clinical success. In the same year, Charles Heidelberger and colleagues synthesized 5-fluorouracil based on the principle of isoelectronicity, also achieving clinical success. These two drugs were the first effective antineoplastic drugs synthesized based on theoretical principles.
In the early 20th century, Paul Ehrlich proposed the concept of a "magic bullet," envisioning specific compounds that could target drugs to disease sites, reducing damage to normal tissues or cells. This was the initial concept of targeted therapies. In 1948, D. Pressman and G. Keightley suggested using antibodies as cell growth inhibitors and carriers for radionuclides, laying the groundwork for targeted antineoplastic drugs and monoclonal antibody-based therapies. In 1951, W.H. Bellwalt used iodine-131-labeled antibodies to treat thyroid tumors. In 1958, Georges Mathé linked antibodies to methotrexate for treating leukemia. In 1972, T. Ghose and colleagues attached chlorambucil to antibodies to treat melanoma. These experiments validated the feasibility of using antibodies as antineoplastic drugs or carriers, but the antibodies used were polyclonal, with limited specificity and efficacy. In 1975, Georges J. F. Köhler and César Milstein developed monoclonal antibody technology. Due to the high specificity of monoclonal antibodies, targeted antineoplastic drugs began to use them as carriers, leading to the development of numerous monoclonal antibody-based antineoplastic drugs.
Research on the antineoplastic bioactivity of metal platinum complexes began in the 1960s when American physiologist Barnett Rosenberg and colleagues, while studying the effects of electromagnetic fields on microorganism growth, discovered that escherichia coli ceased division and proliferation near platinum electrodes in an ammonium chloride medium. Further studies confirmed that cis-dichlorodiammineplatinum(II) and cis-tetrachlorodiammineplatinum(IV) inhibited cell proliferation. Rosenberg and his collaborators conducted experiments on mice with sarcoma-180 and leukemia L1210, demonstrating cisplatin’s anticancer activity, leading to its entry into clinical trials in 1971. In 1978, the FDA approved cisplatin for treating testicular cancer and ovarian cancer. The second-generation platinum complex drug carboplatin was introduced in the 1980s, and the first chiral platinum complex drug, oxaliplatin, was approved in 1996.
In 1962, Monroe Eliot Wall and Mansukh C. Wani, began studying the antineoplastic active components of yew tree bark. Wall extracted paclitaxel from the bark of the Pacific yew (Taxus brevifolia) in 1967, with a yield of only 0.014%. Wani used the extracted paclitaxel to prepare single crystals, determining its chemical structure in 1971 through X-ray scattering techniques. In 1979, biologist Susan Band Horwitz identified paclitaxel’s target as tubulin. In 1984, the National Cancer Institute conducted phase I clinical trials of paclitaxel, which showed excellent efficacy against breast cancer and ovarian cancer. In 1989, Robert Anthony Holton of Florida State University extracted paclitaxel’s precursor, 10-deacetylbaccatin (10-DBA), from the leaves of the European yew, with a yield of about 0.1%, and used it for semi-synthetic production of paclitaxel, addressing the issue of insufficient natural paclitaxel yield.
In the late 1990s, Ciba-Geigy (which merged with Sandoz in 1996 to form Novartis) developed the first molecularly targeted antineoplastic drug, imatinib, through targeted screening. In June 1998, imatinib entered phase I clinical trials, and within weeks, the white blood cell counts of the 31 participating patients returned to normal. Just 32 months later, Novartis submitted a new drug application globally, and on March 27, 2001, the FDA granted it priority review status. On May 10, 2001, imatinib was approved for market by the FDA before completing phase III clinical trials, with the approval process being twice as fast as for similar drugs. The successful development of imatinib pioneered a new model for the development of targeted antineoplastic drugs.
Classification The variety of antineoplastic drugs used in clinical practice is extensive and rapidly evolving, with classification not yet fully standardized. Generally, they are categorized based on their pharmacological actions and targets.
General classification Cytotoxic drugs Drugs directly acting on DNA Alkylating agents (nitrogen mustards, aziridines, mesylate, nitrosourea, etc.) Metal platinum complexes Bleomycins DNA topoisomerase inhibitors (drugs acting on DNA topoisomerase 1, drugs acting on DNA topoisomerase 2-beta) Drugs interfering with DNA Synthesis (Antimetabolites) Folic acid antagonists Pyrimidine antagonists (uracil derivatives, cytosine derivatives) Purine antagonists Multi-target antagonists Drugs acting on structural proteins Drugs inhibiting tubulin polymerization (drugs with one binding site on tubulin, drugs with two binding sites on tubulin) Drugs inhibiting tubulin depolymerization Drugs interfering with ribonucleoprotein function Drugs affecting amino acid supply Non-Cytotoxic Drugs Small-molecule kinase inhibitors Proteasome inhibitors Histone deacetylase inhibitors Monoclonal antibody drugs Antisense oligonucleotide drugs Other antineoplastic drugs Drugs regulating hormone balance Drugs with other antineoplastic mechanisms
Specific drug types + Classification and pharmacological toxicology of antineoplastic drugs English name (Alias) Indications and other uses Mechanism of action Side effectsI. Drugs directly acting on DNA1. Alkylating agentsNitrogen mustards Damage to bone marrow cells, causing bone marrow suppression Damage to intestinal epithelial cells, causing nausea and vomiting Damage to hair epidermal cells, causing hair loss