Antineoplastic

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, 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. 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 and cis-tetrachlorodiammineplatinum 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 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, 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 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

Specific drug types

Mechanism of action

Tumor cell populations include proliferating cells, quiescent cells, and non-proliferative cells. The ratio of proliferating tumor cells to the total tumor cell population is called the growth fraction. The time from the end of one cell division to the end of the next is called the cell cycle, which consists of four phases: pre-DNA synthesis, DNA synthesis, post-DNA synthesis, and mitosis.

Cytotoxic drugs

Cytotoxic drugs exert cytotoxic effects on tumor cells in different phases of the cell cycle and delay phase transitions by affecting biochemical events. Based on their sensitivity to tumor cells in specific phases, cytotoxic drugs are broadly divided into two categories:

Cell cycle non-specific agents : These drugs kill cells in various phases of the proliferative cycle, including G₀ phase cells, such as drugs that directly damage DNA structure or affect its replication or transcription functions. These drugs often have a strong effect on malignant tumor cells, rapidly killing them in a dose-dependent manner, with effects increasing exponentially within the body’s tolerable toxicity limits.
Cell cycle specific agents : These drugs are sensitive only to specific phases of the proliferative cycle and not to G₀ phase cells, such as antimetabolites acting on S-phase cells and vinblastine drugs acting on M-phase cells. These drugs have a weaker effect on tumor cells, with time-dependent cytotoxicity, requiring a certain duration to take effect, and their efficacy does not increase beyond a certain dose.
Non-cytotoxic drugs

Non-cytotoxic drugs primarily target key regulatory molecules in tumor molecular pathology processes. Examples include hormones or their antagonists that alter hormone imbalance; protein tyrosine kinase inhibitors, farnesyltransferase inhibitors, MAPK signaling pathway inhibitors, and cell cycle regulators targeting cell signal transduction molecules; monoclonal antibodies targeting proliferation-related cell signal transduction receptors; angiogenesis inhibitors that disrupt or inhibit new blood vessel formation, effectively preventing tumor growth and metastasis; anti-metastatic drugs that reduce cancer cell shedding, adhesion, and basement membrane degradation; and inhibitors targeting telomerase to promote differentiation of malignant tumor cells.

Toxicology

Currently, clinically used cytotoxic drugs lack ideal selectivity for tumor cells versus normal cells, meaning that while killing malignant tumor cells, they also cause some degree of damage to normal tissues. Toxic reactions are a key factor limiting the dosage used in chemotherapy and also affect patients’ quality of life. Some molecularly targeted drugs in non-cytotoxic drugs, such as tumor signaling pathway inhibitors, can specifically target certain molecular sites in tumor cells that are typically not expressed or minimally expressed in normal cells. Therefore, non-cytotoxic drugs generally have high safety, good tolerability, and milder toxic reactions.