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.

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. |alt=Chemical structure of Oxaliplatin]] 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. drugs disrupt tumor cells by affecting one or more phases of the cell cycle but lack specificity, resulting in significant toxicity.|alt=Cell cycle diagram]] Tumor cell populations include proliferating cells, quiescent cells (G 0 phase), and non-proliferative cells. The ratio of proliferating tumor cells to the total tumor cell population is called the growth fraction (GF). 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 (G 1 phase), DNA synthesis (S phase), post-DNA synthesis (G 2 phase), and mitosis (M phase). is a side effect of paclitaxel; shown is a skin allergic reaction in a patient after three days of 100 mg/m 2 dosing.|alt=Allergic skin reaction from paclitaxel]] Cardiac toxicity: Most common with doxorubicin, which can cause myocardial degeneration and interstitial edema. Cardiac toxicity may be related to doxorubicin-induced free radical generation. Respiratory system toxicity: Primarily manifests as interstitial pneumonia and pulmonary fibrosis, with key drugs including bleomycin, carmustine, mitomycin C, methotrexate, and gefitinib. Long-term high-dose bleomycin use can cause interstitial pneumonia and pulmonary fibrosis, possibly due to the lack of bleomycin-inactivating enzymes in lung endothelial cells. Liver toxicity: Some cytotoxic drugs, such as L-asparaginase, dactinomycin, and cyclophosphamide, can cause liver damage. Urinary system toxicity: High-dose cyclophosphamide can cause hemorrhagic cystitis, possibly due to large amounts of the metabolite acrolein excreted through the urinary tract; co-administration of mesna can prevent this. Cisplatin, secreted by renal tubules, can damage proximal and distal tubules. Maintaining adequate urine output can help reduce urinary system toxicity. Neurotoxicity: Vincristine is most likely to cause peripheral neuropathy. Cisplatin, methotrexate, and 5-fluorouracil may occasionally cause some neurotoxicity. Hypersensitivity reaction: Antineoplastic drugs that are polypeptides or proteins, such as L-asparaginase and bleomycin, are likely to cause hypersensitivity reactions when administered intravenously. Paclitaxel’s hypersensitivity reactions may be related to the excipient polyoxyethylated castor oil. Tissue necrosis and deep vein thrombosis: Highly irritating drugs, such as mitomycin C and doxorubicin, can cause thrombophlebitis at the injection site, and extravasation of the injection solution can lead to local tissue necrosis, necessitating proper injection techniques. s and other small molecules, are commonly used as targeted drug carriers. |alt=Liposome structure]] Due to the lack of selectivity of cytotoxic drugs, they cause significant side effects. In addition to developing new non-cytotoxic drugs to reduce side effects, modifying the dosage forms of cytotoxic drugs is an important strategy. In 1906, Paul Ehrlich proposed the concept of targeted drug systems. Targeted formulations, considered the fourth generation of drug dosage forms, are deemed suitable for antineoplastic drugs. These formulations enhance the specificity of non-cytotoxic drugs and confer selectivity to cytotoxic drugs. Early targeted formulations were primarily passive. In 1961, British hematologist Alec Bangham invented liposomes. In 1971, liposomes were first used as drug carriers, marking the earliest passive targeted formulation. Liposomes enable drugs to selectively kill or inhibit cancer cell proliferation, increasing selectivity for lymphoid tissues. Since tumor cells contain higher concentrations of phosphatases and acylases than normal cells, encapsulating anticancer drugs in liposomes facilitates drug release due to enzymatic action and enhances drug retention in target areas. Active targeted formulations include modified drug carriers (e.g., ibuprofen zinc microemulsion), prodrugs (e.g., cyclophosphamide), and drug-macromolecule complexes. Due to their higher selectivity, active targeted formulations deliver drugs directly to the target area, enhancing therapeutic efficacy. With advances in molecular biology, research on physicochemical targeted formulations has deepened. These include magnetic targeted formulations, embolism targeted formulations, thermosensitive targeted formulations, and pH-sensitive targeted formulations. Magnetic targeted formulations encapsulate drugs with ferromagnetic materials in polymeric carriers, guided by external magnetic fields for targeted delivery and localization in the body, primarily used as anticancer drug carriers. Embolism targeted formulations block blood supply and nutrients to the target area, causing ischemic necrosis of cancer cells. Embolism formulations containing antineoplastic drugs combine embolization with targeted chemotherapy. pH-sensitive formulations exploit the significantly lower pH of tumor interstitial fluid compared to surrounding normal tissues for targeted therapy. , are a key focus in new drug development. |alt=Imatinib chemical structure]] With a deeper understanding of tumor pathogenesis and the regulation of cell differentiation, proliferation, and apoptosis at the molecular level, antineoplastic drugs have shifted from traditional cytotoxic effects to targeting multiple molecular pathways. Newly marketed molecular targeted antineoplastic drugs can be divided into small molecule chemical drugs and biotechnology drugs. The former primarily consist of various small molecule kinase inhibitors, alongside proteasome inhibitors and some epigenetic drugs. The latter, represented by monoclonal antibody drugs, are increasingly becoming a cornerstone of cancer therapy. These drugs surpass traditional direct cytotoxic agents. The development of molecular targeted antineoplastic drugs is currently a hot topic in drug development.

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