Antineoplastic agents, also known as anticancer drugs or antineoplastic drugs, are medications used to treat malignant tumors. 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. 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 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 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. developed the first molecularly targeted antineoplastic drug, imatinib, through targeted screening.
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
{| class="wikitable"
|-
| rowspan="3" | 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
|-
| rowspan="2" | 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
{| class="wikitable mw-collapsible mw-collapsed" width="100%" style="margin:1em auto;"
|+ Classification and pharmacological toxicology of antineoplastic drugs
|-
| Diethylstilbestrol|| Menopausal breast cancer || rowspan="14" | Regulates hormone balance, inhibiting certain hormone-dependent cancers, serving as adjuvant therapy || rowspan="14" | (See Genitourinary system and sex steroids, Endocrine therapy, Glucocorticoid, Corticosteroid, etc.)
|-
| Methyltestosterone|| rowspan="3" | Advanced breast cancer with bone metastasis
|-
| Testosterone Propionate
|-
| Fluoxymesterone
|-
| Medroxyprogesterone (MPA) || Breast cancer, kidney cancer, endometrial cancer
|-
| Prednisone|| Adjuvant therapy for Hodgkin lymphoma and lymphoma
|-
| Tamoxifen (TAM) || Breast cancer
|-
| Goserelin|| Prostate cancer, menopausal breast cancer
|-
| Leuprorelin|| Pre-menopausal and estrogen receptor-positive prostate cancer and breast cancer
|-
| Flutamide|| Prostate cancer
|-
| Toremifene|| Menopausal estrogen receptor-positive metastatic breast cancer
|-
| Letrozole|| Postmenopausal advanced breast cancer
|-
| Anastrozole|| Adjuvant therapy for postmenopausal breast cancer
|-
| Aminoglutethimide (AG) || Postmenopausal advanced breast cancer
|-
! colspan="4" |5. Drugs with other antineoplastic mechanisms
|-
| Endostar (Rh-Endostatin) || Adjuvant therapy for non-small-cell lung cancer|| Inhibits proliferation and migration of tumor vascular endothelial cells, thereby suppressing tumor angiogenesis ||
- Heart toxicity
- Digestive system toxicity
|-
| Retinoic Acid (Tretinoin) || Acute promyelocytic leukemia || Modulates and degrades the PML-RARα fusion protein’s retinoic acid receptor (RARα) domain, inducing leukocyte differentiation and apoptosis ||
- Infertility and teratogenicity
|-
| Arsenious Acid (As<sub>2</sub>O<sub>3</sub>) || Acute promyelocytic leukemia || Modulates and degrades the PML-RARα fusion protein, downregulates bcl-2 gene expression, inducing leukocyte differentiation and apoptosis ||
- Requires strict dose control, high doses are carcinogenic
|-
| Ubenimex|| Combination therapy with chemotherapy or radiotherapy, elderly immune deficiency, etc. || Competitively inhibits aminopeptidase B and leucine peptidase activity, enhancing T lymphocyte function and NK cell activity. It also promotes colony-stimulating factor synthesis, stimulating bone marrow cell regeneration and differentiation, and interferes with tumor cell metabolism, inhibiting proliferation. ||
- Digestive system toxicity
- Rash
- Transient mild transaminase elevation
|-
| Norcantharidin|| Adjuvant chemotherapy for liver cancer, esophageal cancer, stomach cancer, cirrhosis || Inhibits cancer cell protein synthesis, affecting DNA and RNA synthesis, reduces cancer hormone levels (mainly cyclic guanosine monophosphate-phosphodiesterase), and increases spleen lymphocyte production of interleukin II and macrophage production of interleukin I, enhancing immunity ||
- Digestive system toxicity
- Injectable forms may cause skin reactions
|-
| Cucurbitacin B|| Adjuvant therapy for primary liver cancer || Exhibits multiple biological activities, including liver protection, inhibits STAT3 transcription factor activation, and disrupts the actin cytoskeleton of tumor cells ||
- Gastrointestinal reactions
|-
| EGb761|| Adjuvant therapy for metastatic cancers || Contains over 100 chemical components, with flavonoids and terpene lactones as active ingredients with antitumor activity ||
- Interactions with anticoagulants
|}
Mechanism of action
thumb|[[Cytotoxicity|Cytotoxic 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<sub>0</sub> 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<sub>1</sub> phase), DNA synthesis (S phase), post-DNA synthesis (G<sub>2</sub> phase), and mitosis (M phase). Based on their sensitivity to tumor cells in specific phases, cytotoxic drugs are broadly divided into two categories:
- Cell cycle non-specific agents (CCNSA): These drugs kill cells in various phases of the proliferative cycle, including G<sub>0</sub> phase cells, such as drugs that directly damage DNA structure or affect its replication or transcription functions (e.g., alkylating agents, antitumor antibiotics, and platinum complexes). 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.|alt=Bcr-Abl kinase structure]]
Non-cytotoxic drugs
Non-cytotoxic drugs primarily target key regulatory molecules in tumor molecular pathology processes. 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.
Adverse reactions of cytotoxic drugs
thumb|Hair loss is one of the most visible side effects of cytotoxic drugs.|alt=Patient with hair loss
Common toxic reactions
- Bone marrow suppression: One of the major obstacles in cancer chemotherapy, most cytotoxic drugs, except hormones, bleomycin, and L-asparaginase, cause varying degrees of bone marrow suppression. The likelihood of reduced peripheral blood cell counts after chemotherapy depends on cell lifespan, with shorter-lived peripheral blood cells more likely to decrease, typically starting with leukopenia followed by thrombocytopenia, generally without causing severe anemia. In addition to using colony-stimulating factors such as GM-CSF, G-CSF, M-CSF, and EPO to manage blood cell decline, nursing care must include measures to prevent infections and control bleeding.
Specific toxic reactions
thumb|[[Hypersensitivity|Hypersensitivity reaction is a side effect of paclitaxel; shown is a skin allergic reaction in a patient after three days of 100 mg/m<sup>2</sup> 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.
- Liver toxicity: Some cytotoxic drugs, such as L-asparaginase, dactinomycin, and cyclophosphamide, can cause liver damage.
Small-molecule kinase inhibitors
Due to their high specificity, small-molecule kinase inhibitors have minimal side effects, with gastrointestinal reactions being the most common. The most prominent and common form of resistance is multiple drug resistance (MDR) or pleiotropic drug resistance, where tumor cells develop resistance to multiple structurally and mechanistically diverse antineoplastic drugs after exposure to one drug.|alt=Liposome structure]]
Due to the lack of selectivity of cytotoxic drugs, they cause significant side effects. These formulations enhance the specificity of non-cytotoxic drugs and confer selectivity to cytotoxic drugs.
Early targeted formulations were primarily passive. 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.|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.