Antineoplastic

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Antineoplastic agents
Drug class
Chemotherapy bottles NCI.jpg
Clockwise from center: Bleomycin, vincristine, dacarbazine, cyclophosphamide, doxorubicin, etoposide
Class identifiers
UseTreatment of malignant tumors
ATC code L01
Biological target Killing or inhibiting cancer cells
Clinical data
Drugs.com Drug Classes
External links
MeSH E02.183.750.500
Legal status
In Wikidata

Antineoplastic agents, also known as anticancer drugs or antineoplastic drugs, are medications used to treat malignant tumors. [1] 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. [2] Commonly used antineoplastic drugs include cisplatin, doxorubicin, paclitaxel, and imatinib.

Contents

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. [3]

Uses

Antineoplastic drugs are primarily used in medical settings to treat cancer. [4] Because some antineoplastic drugs also exhibit antiviral activity, they are used to treat certain viral infectious diseases. [5] 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. [3] Additionally, antineoplastic drugs are employed in scientific research to further understand the molecular biology of cancer through studies of their pharmacological effects. [3]

History

Oxaliplatin, the first platinum-based alkylating agent shown to be effective against colorectal cancer Oxaliplatin-2D-skeletal.svg
Oxaliplatin, the first platinum-based alkylating agent shown to be effective against colorectal cancer

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. [1] The first aromatic nitrogen mustard drug, chlorambucil, was approved in 1957 for treating chronic lymphocytic leukemia. [6]

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. [7] In the same year, Charles Heidelberger and colleagues synthesized 5-fluorouracil based on the principle of isoelectronicity, also achieving clinical success. [8] These two drugs were the first effective antineoplastic drugs synthesized based on theoretical principles. [4]

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. [9] In 1951, W.H. Bellwalt used iodine-131-labeled antibodies to treat thyroid tumors. [10] In 1958, Georges Mathé linked antibodies to methotrexate for treating leukemia. In 1972, T. Ghose and colleagues attached chlorambucil to antibodies to treat melanoma. [11] 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. [12]

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. [13] [14] [15] 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. [1]

Due to the excessive harm caused by extracting paclitaxel directly from the bark of the Pacific yew, research on paclitaxel was once stalled. PacificYew 7591.jpg
Due to the excessive harm caused by extracting paclitaxel directly from the bark of the Pacific yew, research on paclitaxel was once stalled.

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. [16] In 1979, biologist Susan Band Horwitz identified paclitaxel’s target as tubulin. [17] In 1984, the National Cancer Institute conducted phase I clinical trials of paclitaxel, which showed excellent efficacy against breast cancer and ovarian cancer. [5] 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. [18] [19] [20] [16]

In the late 1990s, Ciba-Geigy (which merged with Sandoz in 1996 to form Novartis) [21] developed the first molecularly targeted antineoplastic drug, imatinib, through targeted screening. [16] 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. [22]

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. [1] [23] [24]

General classification

Cytotoxic drugsDrugs directly acting on DNA
Drugs interfering with DNA Synthesis (Antimetabolites)
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 Molecularly targeted drugs
Other antineoplastic drugs
  • Drugs regulating hormone balance
  • Drugs with other antineoplastic mechanisms

Specific drug types

Classification and pharmacological toxicology of antineoplastic drugs [6] [1] [23] [24]
English name (Alias)Indications and other usesMechanism of actionSide effects
I. Drugs directly acting on DNA
1. Alkylating agents
Nitrogen mustards
Chlormethine Lymphoma, Hodgkin lymphoma The nitrogen atom in nitrogen mustard drugs is highly basic and, under physiological pH, reacts with the β-chlorine atom to form highly reactive aziridinium ions, which are strong electrophilic alkylating agents. These ions undergo alkylation reactions with nucleophilic groups in DNA, RNA, or proteins, forming cross-links or causing depurination, leading to DNA strand breaks. During subsequent replication, base-pair mismatches occur, damaging DNA structure or function.
Nitrogen mustards
Chlorambucil (Leukeran) Chronic lymphocytic leukemia, lymphoma, Hodgkin lymphoma, ovarian cancer, etc.
Melphalan Ovarian cancer, breast cancer, lymphoma, multiple myeloma, etc.
Uramustine
Formylmelphalan Seminoma, lymphoma, multiple myeloma, etc.
Cyclophosphamide (CTX) Lymphoma, acute lymphoblastic leukemia, multiple myeloma, lung cancer, neuroblastoma, etc.
Ifosfamide (IFO) Testicular cancer, lymphoma, sarcoma, bladder cancer, etc.
Chlorophosphamide Hodgkin lymphoma, chronic lymphocytic leukemia, etc.
Aziridines
Thiotepa Ovarian cancer, breast cancer, liver cancer, bladder cancer, etc.Similar to nitrogen mustards, acting as active intermediates formed after nitrogen mustard metabolism.
Mitomycin C Various adenocarcinomas such as stomach cancer, breast cancer, pancreatic cancer, etc.
Nitrosoureas
Carmustine (BCNU) Brain tumor, metastatic tumor, etc.In nitrosoureas, the presence of the N-nitroso group destabilizes the bond between the nitrogen atom and the adjacent carbonyl group, decomposing under physiological conditions to form electrophilic groups that undergo alkylation reactions with DNA bases and phosphate groups.
Lomustine (CCNU)
Semustine (Me-CCNU) Brain tumor, stomach cancer, colorectal cancer, lung cancer, etc.
Nimustine (ACNU) Brain tumor, stomach cancer, colorectal cancer, lung cancer, Hodgkin lymphoma, etc.
Ranimustine Glioblastoma, multiple myeloma, chronic myelogenous leukemia, Hodgkin lymphoma, etc.
Streptozotocin Islet cell tumor, etc.
Chlorozotocin
Mesylate (methyl sulfonates)
Busulfan Chronic myelogenous leukemia, myeloproliferative disorders, etc.Binds to guanine in DNA, causing intramolecular cross-linking, and undergoes dialkylation with thiol groups in amino acids.
Other alkylating agents
Altretamine Combination chemotherapy for ovarian cancer, small cell lung cancer, etc.Metabolized to produce active N-(hydroxymethyl)melamine, which further demethylates in cells to form electrophilic groups that alkylate DNA.
Procarbazine Hodgkin lymphoma, multiple myeloma, melanoma, etc.Metabolized to release methyl cations that alkylate DNA, while other metabolites, structurally similar to intermediates in purine biosynthesis, interfere with purine biosynthesis.
Dacarbazine Melanoma, Hodgkin lymphoma, etc.Metabolized to release methyl cations that alkylate DNA, while other metabolites interfere with purine biosynthesis.
Trabectedin (Yondelis) Soft-tissue sarcoma A special alkylating agent that acts on the grooves between DNA double helices, interfering with cell division and DNA repair by binding to DNA, thereby promoting tumor cell apoptosis.
2. Metal platinum complexes
Cisplatin (DDP)Non-spermatogonia testicular cancer, ovarian cancer, etc., with a broad antitumor spectrumPlatinum complexes hydrolyze into hydrates upon entering tumor cells, forming a closed five-membered chelate ring by coordinating with the N-7 position of two guanine bases in DNA, disrupting hydrogen bonds between purine and cytosine bases on nucleotide chains, altering the normal double-helix structure of DNA, causing local denaturation and loss of replication ability.
Carboplatin (CBP)
Oxaliplatin
Nedaplatin
3. Bleomycins
Bleomycin (BLM) Squamous-cell carcinoma (head and neck, upper digestive tract, reproductive system, etc.), combination therapy for lymphoma, etc.The chemical structure of bleomycin drugs includes a left portion with multiple amino acids, sugars, pyrimidine rings, and imidazole, and a right portion with a planar bithiazole ring. When interacting with DNA, the left portion forms a chelate with ferrous ions, activating the drug and binding to the C-4' of thymidine deoxynucleotide in DNA, causing DNA strand breaks; the right portion binds to specific parts of DNA’s minor groove, leading to DNA cleavage.
Pingyangmycin (PYM) Squamous-cell carcinoma (head and neck), combination therapy for lymphoma, breast cancer, etc.
4. DNA topoisomerase inhibitors
Drugs acting on topoisomerase (Topo I)
Camptothecin (CPT)Gastrointestinal tumors, liver cancer, bladder cancer, leukemia, etc.Primarily camptothecin-based drugs, whose chemical structure contains a β-hydroxy lactone ring that reacts with topoisomerase, preventing the DNA single-strand break-rejoining reaction, thus inhibiting DNA transcription, replication, and cell mitosis.
Irinotecan (CPT-11) Lung cancer, colorectal cancer, ovarian cancer, uterine cancer, leukemia, etc.
Topotecan Small-.cell lung cancer, colorectal cancer, breast cancer, etc.
Rubitecan Small-cell lung cancer, colorectal cancer, breast cancer, etc.
Drugs acting on toposoimerase 2 (Topo II)
Dactinomycin (DACT)Malignant hydatidiform mole, Hodgkin lymphoma, choriocarcinoma, kidney cancer Its planar phenoxazinone core binds to DNA, while inhibiting toposoimerase 2.
Doxorubicin (Adriamycin, ADM)Drug-resistant acute lymphoblastic leukemia, Hodgkin lymphoma, breast cancer, stomach cancer, etc.The drug’s anthracycline or anthraquinone structure intercalates between DNA C-G base pairs, rigidifying the DNA-toposoimerase 2 complex, ultimately causing DNA strand breaks.
Daunorubicin (Daunomycin, DRN)
Epirubicin
Zorubicin
Aclacinomicin A
Pirarubicin
Amsacrine (AMSA)
Mitoxantrone (NVT)Advanced breast cancer, relapsed non-Hodgkin lymphoma, etc.
Pixantrone
Etoposide (VePesid, VP16) Lung cancer, testicular cancer A group obtained through epimerization at position 4 directly interacts with toposoimerase 2, preventing DNA replication and transcription.
Teniposide (VM-26) Lung cancer, testicular cancer, etc.
Amonafide (BIDA) Small-cell lung cancer A toposoimerase 2 inhibitor, selectively blocking DNA replication.
II. Drugs interfering with DNA synthesis
1. Folic acid antagonists
Methotrexate (Amethopterine, MTX) Acute leukemia, choriocarcinoma, etc.Structurally similar to dihydrofolic acid, it acts on dihydrofolate reductase, preventing the conversion of dihydrofolic acid to tetrahydrofolic acid, affecting coenzyme F production and interfering with thymidylate and purine nucleotide synthesis.
Aminopterin
2. Pyrimidine antagonists
Uracil derivatives
5-Fluorouracil (5-FU) Acute leukemia, choriocarcinoma, etc.These drugs are metabolized in the body to 5-fluorodeoxyuridine monophosphate, which binds to thymine synthase and interacts with coenzyme 5,10-methylenetetrahydrofolic acid. The stable C-F bond prevents effective thymidylate deoxynucleotide synthesis, inhibiting DNA synthesis.
Tegafur (Ftorafur)
Difuradin
Doxifluridine (5'-dFUR) Stomach cancer, colorectal cancer, breast cancer, etc.
Carmofur
Cytosine derivatives
Cytarabine (Ara-C) Acute myelogenous leukemia, monocytic leukemia, etc.Similar to uracil derivatives, inhibiting DNA polymerase.
Enocitabine
CyclocytidineVarious acute leukemias, anti-herpes simplex virus (as an antiviral drug), etc.
Gemcitabine Pancreatic cancer, advanced small cell lung cancer, etc.
Decitabine Various acute leukemias Inhibits DNA methyltransferase (DNMT).
3. Purine antagonists
Mercaptopurine (6-MP)Maintenance therapy for acute lymphoblastic leukemia, choriocarcinoma, etc.These drugs are enzymatically converted to 6-thioinosinic acid, inhibiting adenylosuccinate synthetase, preventing inosinic acid conversion to adenosine monophosphate; they also inhibit inosinate dehydrogenase, preventing inosinic acid oxidation to xanthine nucleotide, thus inhibiting DNA and RNA synthesis.
Sulfomercaptopurine Sodium
Azathioprine (6-AP) Leukemia (discontinued), lupus erythematosus, organ transplant (as an immunosuppressant), etc.
6-Tioguanine (6-TG)Combination therapy for leukemia, etc.
Pentostatin
Fludarabine Cutaneous T-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, etc.
Cladribine
Nelarabine T-cell acute lymphoblastic leukemia, T-cell lymphoma
4. Multi-target antagonists and other antimetabolites
Raltitrexed Advanced colorectal cancer, etc.Combines the effects of folic acid antagonists and uracil derivative drugs.
Pemetrexed Non-small-cell lung cancer, drug-resistant mesothelioma
Hydroxycarbamide (Hydroxyurea, HU) Chronic myelogenous leukemia, head and neck cancer, ovarian cancer, etc.Inhibits nucleotide reductase, preventing cytidine monophosphate conversion to deoxycytidine monophosphate, thus inhibiting DNA synthesis, selectively acting on S-phase cells.
III. Drugs acting on structural proteins
1. Drugs inhibiting tubulin polymerization
Drugs with one binding site on tubulin
Colchicine Breast cancer (discontinued), gout, rheumatoid arthritis (as an immunosuppressant), etc.The seven-membered fused ring in the drug’s structure binds to a site between the α and β subunits of the tubulin dimer, blocking cell division.
Drugs with two binding sites on tubulin
Vinblastine (VLB)Various solid tumorsThe dimeric indole structure binds to undamaged tubulin at the “growth end,” with a low-affinity site on the microtubule wall, causing microtubules to aggregate into clusters within cells, halting tumor cells in metaphase.
Vincristine (VCR)Pediatric acute leukemia, etc.
Vindesine (VDS) Acute lymphoblastic leukemia, chronic myelogenous leukemia, etc.
Vinorelbine (NRB)Non-small-cell lung cancer, etc.
2. Drugs inhibiting tubulin depolymerization
Paclitaxel (Taxol) Ovarian cancer, breast cancer, lung cancer, melanoma, etc.Induces and promotes tubulin polymerization while inhibiting the depolymerization of formed microtubule bundles, producing stable microtubule bundles and disrupting their dynamic regeneration.
Docetaxel (Taxotere)Solid tumors except kidney cancer and colorectal cancer
3. Drugs interfering with ribonucleoprotein function
HarringtonineAcute monocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, etc.Inhibits the initial stage of protein synthesis, causing ribonucleoprotein breakdown.
Homoharringtonine
4. Drugs affecting amino acid supply
L-Asparaginase Combination therapy for acute lymphoblastic leukemia, etc.Hydrolyzes serum asparagine, depriving cancer cells of asparagine supply, inhibiting their growth.
IV. Small-molecule kinase inhibitors
1. Single-target kinase inhibitors
Imatinib (Glivec, Gleevec) Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumor Binds to the ATP site of Abl protein kinase, inhibiting kinase activity, preventing proliferation and inducing apoptosis in Bcr-Abl-positive cells.
Dasatinib (Sprycel)
Nilotinib (Tasigna)
Bosutinib
Ponatinib
Gefitinib (Iressa)Second-line treatment for advanced or metastatic non-small-cell lung cancer Binds to the intracellular kinase domain, blocking EGFR (epidermal growth factor receptor tyrosine kinase) activity and downstream signaling pathways.
Erlotinib (Tarceva)
Icotinib
Afatinib
Temsirolimus (Torisel)Advanced kidney cancer Blocks the PI3K-Akt-mTOR signaling pathway and other mTOR-mediated signal transduction processes.
  • Occasional adverse reactions
Everolimus (Afinitor)
Vemurafenib Unresectable or metastatic melanoma with BRAF V600E mutationBlocks B-Raf kinase
Dabrafenib
Ibrutinib Mantle cell lymphoma, chronic lymphocytic leukemia, macroglobulinemia Blocks BTK protein tyrosine kinase
Idelalisib Refractory acute lymphoblastic leukemia, refractory follicular B-cell non-Hodgkin lymphoma, refractory small lymphocytic lymphoma Blocks PI3Kδ lipid kinase
Osimertinib Non-small-cell lung cancer Inhibits EGFR protein tyrosine kinase
2. Multi-target kinase inhibitors
Sorafenib (Nexavar) Kidney cancer, liver cancer, etc.Blocks the Ras/Raf/MEK/ERK signaling pathway while inhibiting VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet-derived growth factor receptor) tyrosine kinase activity.
Sunitinib (Sutent)Advanced kidney cancer, gastrointestinal stromal tumor, advanced pancreatic cancer Blocks the ATP-binding sites of VEGFR1/2/3 and PDGFR intracellular tyrosine kinase domains, while inhibiting c-kit (stem cell factor receptor), RET (glial cell-derived neurotrophic factor receptor), CSF-1R (colony-stimulating factor receptor-1), and other protein tyrosine kinases.
Pazopanib (Votrient)Advanced kidney cancer, advanced soft-tissue sarcoma Inhibits VEGFR-1/2/3, PDGFR-α/β, and c-kit protein tyrosine kinases
Vandetanib (Zactima)Advanced or metastatic medullary thyroid cancer Inhibits VEGFR, EGFR, and RET protein tyrosine kinases
Lapatinib (Tykerb)Advanced or metastatic breast cancer Inhibits ErbB1/EGFR and ErbB2/HER2 protein tyrosine kinases
Crizotinib ALK-positive metastatic non-small-cell lung cancer Inhibits ALK, C-MET, and HGFR protein tyrosine kinases
Ruxolitinib Moderate or high-risk primary myelofibrosis Inhibits JAK1 and JAK2 protein tyrosine kinases
Axitinib Primary myelofibrosis, polycythemia vera Inhibits VEGFR, C-KIT, PDGFR, and other protein tyrosine kinases
Regorafenib Metastatic colorectal cancer, advanced gastrointestinal stromal tumor Inhibits VEGFR and other protein tyrosine kinases
Cabozantinib Progressive or metastatic medullary thyroid cancer Inhibits VEGFR and C-MET protein tyrosine kinases
Trametinib Unresectable or metastatic melanoma with BRAF V600E mutationInhibits MEK1 and MEK2 serine/threonine kinases
  • Occasional adverse reactions
Ceritinib ALK-positive metastatic non-small-cell lung cancer Inhibits ALK and other protein tyrosine kinases
Palbociclib Advanced breast cancer in postmenopausal women with ER-positive and HER2-negative statusInhibits CDK4 and CDK6 serine/threonine kinases
  • Occasional adverse reactions
Lenvatinib Locally recurrent or metastatic, progressive, and radio-resistant differentiated thyroid tumor, liver cancer Inhibits VEGFR, PDGFR, and other protein tyrosine kinases
V. Other antineoplastic drugs
1. Proteasome inhibitors
Bortezomib (Velcade) Multiple myeloma Inhibits chymotrypsin and trypsin of the proteasome 26S subunit
Carfilzomib
2. Histone deacetylase inhibitors
Vorinostat (SAHA)Cutaneous T-cell lymphoma Inhibits histone deacetylase (HDAC)-1/2/3/6
  • Occasional adverse reactions
3. Monoclonal antibody drugs
Rituximab (Rituxan) Non-Hodgkin lymphoma Binds to CD20 antigen, causing B lymphocyte lysis
Alemtuzumab (Campath) Chronic lymphocytic leukemia Binds to CD52 antigen, causing apoptosis of CD52-positive target cells
Ibritumomab (Zevalin)Relapsed or refractory non-Hodgkin lymphoma Carries the radioactive isotope 90Y, binding to CD20 antigen, concentrating 90Y at tumor sites and killing tumor cells within a 5mm range via beta radiation
Tositumomab (Bexxar) Non-Hodgkin lymphoma Carries the radioactive isotope 131I, binding to CD20 antigen, killing tumor cells via 131I radioactivity
Trastuzumab (Herceptin)Metastatic breast cancer with high HER-2 (epidermal growth factor receptor) expressionSelectively binds to HER-2 (ErbB-2), blocking HER-2-mediated PI3K and MAPK signaling pathways, inhibiting proliferation of HER-2-overexpressed tumor cells
Cetuximab (Erbitux)Metastatic colorectal cancer, head and neck tumorsInhibits tumor proliferation mediated by EGFR signaling pathways
Panitumumab (Vectibix)Metastatic colorectal cancer
Nimotuzumab Stage III/IV nasopharyngeal carcinoma with HER-1-positive expression
Pertuzumab (Perjeta) Breast cancer with HER-2-positive expression
Bevacizumab (Avastin)Metastatic colorectal cancer, advanced non-small cell lung cancer, metastatic kidney cancer, malignant glioma Binds to VEGF (vascular endothelial growth factor), preventing VEGF from binding to its receptors (KDR and Flt-1) on tumor vascular endothelial cells, inhibiting tumor angiogenesis
Ipilimumab (Yervoy) Melanoma, lung cancer Inhibits CTLA4
  • Occasional adverse reactions
Pembrolizumab (Keytruda) Melanoma, non-small-cell lung cancer Inhibits PD1
4. Drugs regulating hormone balance [Note 1]
Diethylstilbestrol Menopausal breast cancer Regulates hormone balance, inhibiting certain hormone-dependent cancers, serving as adjuvant therapy(See Genitourinary system and sex steroids, Endocrine therapy, Glucocorticoid, Corticosteroid, etc.)
Methyltestosterone 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
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
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
Arsenious Acid (As2O3)Acute promyelocytic leukemia Modulates and degrades the PML-RARα fusion protein, downregulates bcl-2 gene expression, inducing leukocyte differentiation and apoptosis
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.
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
Cucurbitacin B Adjuvant therapy for primary liver cancerExhibits 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 cancersContains over 100 chemical components, with flavonoids and terpene lactones as active ingredients with antitumor activity

Mechanism of action

Cytotoxic drugs disrupt tumor cells by affecting one or more phases of the cell cycle but lack specificity, resulting in significant toxicity. Animal cell cycle-en.svg
Cytotoxic drugs disrupt tumor cells by affecting one or more phases of the cell cycle but lack specificity, resulting in significant toxicity.

Tumor cell populations include proliferating cells, quiescent cells (G0 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 (G1 phase), DNA synthesis (S phase), post-DNA synthesis (G2 phase), and mitosis (M phase). [4]

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. [25] Based on their sensitivity to tumor cells in specific phases, cytotoxic drugs are broadly divided into two categories:

  1. Cell cycle non-specific agents (CCNSA): 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 (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. [23]
  2. Cell cycle (phase) specific agents (CCSA): 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. [23]
Bcr-Abl kinase is one of the targets of protein tyrosine kinase inhibitors and was the first specific target identified. Bcr abl STI 1IEP.png
Bcr-Abl kinase is one of the targets of protein tyrosine kinase inhibitors and was the first specific target identified.

Non-cytotoxic drugs

Non-cytotoxic drugs primarily target key regulatory molecules in tumor molecular pathology processes. [3] 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. [23]

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. [27] 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. [28]

Adverse reactions of cytotoxic drugs

Hair loss is one of the most visible side effects of cytotoxic drugs. Young girl receiving chemotherapy.jpg
Hair loss is one of the most visible side effects of cytotoxic drugs.

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. [28]
  • Gastrointestinal reactions: The most common toxic reaction of cytotoxic drugs. Chemotherapy-induced nausea and vomiting are classified into acute (within 24 hours of chemotherapy) and delayed (after 24 hours). For high or moderate emetogenic drugs, dexamethasone and 5-HT3 receptor antagonists (e.g., ondansetron) may be used, while mild emetogenic drugs can be managed with metoclopramide or chlorpromazine. Chemotherapy can also damage rapidly proliferating gastrointestinal mucosal tissues, easily causing stomatitis, oral ulcers, glossitis, and esophagitis, necessitating attention to oral hygiene to prevent infections. [28]
  • Hair loss: Normal human scalp has about 100,000 hairs, with 10%–15% of hair-generating cells in the resting phase, while the majority are actively growing, making most cytotoxic drugs capable of causing varying degrees of hair loss. During chemotherapy, using an ice cap to cool the scalp, causing local vasoconstriction, or applying a tourniquet at the hairline can reduce drug delivery to hair follicles, mitigating hair loss. Hair can regrow after chemotherapy cessation. [29]

Specific toxic reactions

Hypersensitivity reaction is a side effect of paclitaxel; shown is a skin allergic reaction in a patient after three days of 100 mg/m dosing. Syndrome Main Pied 1.jpg
Hypersensitivity reaction is a side effect of paclitaxel; shown is a skin allergic reaction in a patient after three days of 100 mg/m dosing.

Long-term toxic reactions

  • Second primary malignant tumors: Many antineoplastic drugs, particularly alkylating agents, are mutagenic and carcinogenic, and have immunosuppressive effects. In patients who achieve long-term survival after chemotherapy, some may develop second primary malignant tumors potentially related to chemotherapy. [27]
  • Infertility and teratogenicity: Many antineoplastic drugs, especially alkylating agents, can affect germ cell production and endocrine function, causing infertility and teratogenic effects. In male patients, testicular germ cell numbers significantly decrease, leading to male infertility; in female patients, permanent ovarian dysfunction and amenorrhea may occur, and in pregnant women, miscarriage or teratogenesis may result. [30]

Adverse reactions of non-cytotoxic drugs

Non-cytotoxic drugs have milder toxic reactions but still exhibit some side effects. [30]

Monoclonal antibody drugs

Monoclonal antibody drugs are classified into murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully humanized monoclonal antibodies. Murine monoclonal antibodies (drugs with “-momab” as the generic name suffix) have good specificity and rapid metabolism but, due to their lack of humanized components, induce human anti-mouse antibodies, resulting in significant side effects. [31] Due to these significant side effects, no new murine monoclonal antibody drugs have entered clinical research since 2003. [22] Chimeric monoclonal antibodies (drugs with “-ximab” as the generic name suffix) are composed of the variable (V) region of murine monoclonal antibodies spliced with the constant (C) region of human antibodies, with human components accounting for 60%–70%, reducing side effects while retaining antigen-binding specificity. [31] Humanized monoclonal antibodies (drugs with “-zumab” or “-umab” as the generic name suffix) replace the CDR of human antibodies with that of murine monoclonal antibodies, with human components accounting for about 90%, further reducing side effects but slightly decreasing antigen-binding capacity. [31] Fully humanized monoclonal antibodies (drugs with “-mumab” or “-umab” as the generic name suffix) are produced by gene knockout technology, replacing mouse antibody genes with human antibody genes, followed by immunization with antigens and hybridoma techniques. With 100% human components, they have minimal side effects and unaffected therapeutic efficacy. [31]

Small-molecule kinase inhibitors

Due to their high specificity, small-molecule kinase inhibitors have minimal side effects, with gastrointestinal reactions being the most common. [28] Inhibitors targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR), such as gefitinib, can affect the patient’s circulatory system, leading to hypertension and high blood sugar side effects. [1]

Drug resistance

Tumor cells developing resistance to antineoplastic drugs is a major cause of chemotherapy failure. [2] Some tumor cells exhibit natural resistance, where they are inherently insensitive to certain drugs, such as G0 phase tumor cells, which are generally insensitive to most antineoplastic drugs. Other tumor cells develop acquired resistance, becoming insensitive to drugs they were initially sensitive to after a period of treatment. [32] 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. [27] The mechanisms of drug resistance are complex, varying by drug and involving multiple resistance mechanisms for the same drug. The genetic basis of resistance has been established, with tumor cells having a fixed mutation rate during proliferation, each mutation potentially leading to resistant tumor strains. Thus, the larger the tumor (i.e., the more divisions), the greater the chance of resistant strains emerging. The tumor stem cell hypothesis suggests that tumor stem cells are a primary cause of chemotherapy failure, with drug resistance being one of their characteristics. [4] Modern research indicates that tumor cells are more likely to develop resistance to molecularly targeted drugs. [27]

Pharmaceutics

Liposomes, composed of phospholipids and other small molecules, are commonly used as targeted drug carriers. Liposome scheme-en.svg
Liposomes, composed of phospholipids and other small molecules, are commonly used as targeted drug carriers.

Due to the lack of selectivity of cytotoxic drugs, they cause significant side effects. [2] 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. [34] These formulations enhance the specificity of non-cytotoxic drugs and confer selectivity to cytotoxic drugs.

Early targeted formulations were primarily passive. [12] In 1961, British hematologist Alec Bangham invented liposomes. [35] [36] [37] In 1971, liposomes were first used as drug carriers, marking the earliest passive targeted formulation. [38] [39] 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. [40] [41] 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. [12]

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. [12]

Preparation methods

Most antineoplastic drugs are industrially prepared through total or semi-synthesis, while a few drugs (e.g., polypeptide or protein-based antineoplastic drugs) are produced on a large scale through biopharmaceutical methods or natural component extraction. [1]

Future development

Molecular targeted antineoplastic drugs, such as imatinib, are a key focus in new drug development. Imatinib.svg
Molecular targeted antineoplastic drugs, such as imatinib, are a key focus in new drug development.

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. [16] 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. [6] The development of molecular targeted antineoplastic drugs is currently a hot topic in drug development. [15]

Target-based drug development

Current methods for developing targets for antineoplastic drugs include: identifying targets from effective monomeric compounds; discovering targets based on differences in gene expression between normal and pathological tissues; identifying targets through quantitative analysis and comparative studies of changes in protein expression profiles in normal versus diseased states; discovering targets based on protein interactions; and using RNA interference technology to specifically suppress the expression of different genes in cells, identifying targets through changes in cellular phenotype. The development of new antineoplastic drugs involves using the three-dimensional structure of targets, employing computer-aided drug design to rapidly screen for lead compounds, and subsequently obtaining the target drug. The primary targets for new targeted antineoplastic drugs are divided into genomics and proteomics. Currently, targeted antineoplastic drugs focus on two main types of driver genes: one is receptor molecules located on the cell membrane (e.g., HER2/neu), and the other is molecules in key intracellular signaling pathways (e.g., EGFR). Mutations such as insertions, deletions, rearrangements, or amplifications activate driver genes, conferring adaptability to cancer cells, thus driving cancer development and progression. Protein targets for targeted antineoplastic drugs mainly include disease-specific proteins (e.g., polypeptide Op18, heat shock protein 70), biomarker molecules (e.g., cellular keratin CK19), and enzyme molecules (e.g., histone deacetylase (HDAC)).

See also

Notes

  1. ↑ Strictly speaking, these drugs belong to endocrine therapy drugs (ATC code L02), but due to their widespread use in cancer treatment, they are listed here.

References

  1. 1 2 3 4 5 6 7 Peng, Sixun; You Qidong (2015). Yàowù huàxué药物化学[Medicinal Chemistry] (in Chinese) (Third ed.). Beijing: Chemical Industry Press. pp. 487–521. ISBN   978-7-122-24850-3.
  2. 1 2 3 Jiāng Yuǎnyīng; Wén Àidōng. Línchuáng yàowù zhìliáo xué临床药物治疗学[Clinical Pharmacotherapy] (in Chinese) (4th. ed.). People’s Medical Publishing House. ISBN   978-7-117-22028-6.
  3. 1 2 3 4 Li Jun (March 2013). Línchuáng Yàolǐxué临床药理学 [Clinical Pharmacology] (in Chinese) (Fifth ed.). Beijing: People's Medical Publishing House. ISBN   978-7-117-16993-6 . Retrieved August 13, 2025.
  4. 1 2 3 4 Wang Guanjun; He Jie (2013). Zhǒng liú xué gài lùn肿瘤学概论[Introduction to Oncology] (in Chinese). Beijing: People's Medical Publishing House. pp. 21–24, 116–125. ISBN   978-7-117-17452-7.
  5. 1 2 Patrick G. L. (2013). An Introduction to Medicinal Chemistry (5th ed.). Oxford: Oxford University Press. pp. 514–578. ISBN   978-0-19-969739-7.
  6. 1 2 3 4 5 You Qidong; Sun Tiemin (February 2016). Yào wù huà xué药物化学 [Medicinal Chemistry] (in Chinese) (8th ed.). Beijing: People's Medical Publishing House. pp.  271–304. ISBN   978-7-117-22151-1 . Retrieved August 13, 2025.
  7. ↑ Arnold H.; Bourseaux F.; Brock N. (1958). "Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B 518-ASTA) in experimental tumours of the rat". Nature. 181 (4613): 931. PMID   13526741.
  8. ↑ Heidelberger C.; Chaudhuri N. K.; Danneberg P.; et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature. 179 (4561): 663–666. doi:10.1038/179663a0. PMID   13418758.
  9. ↑ Pressman, D.; Keighley, G. (1948). "The zone of activity of antibodies as determined by the use of radioactive tracers; the zone of activity of nephritoxic antikidney serum". Journal of Immunology (Baltimore, Md.: 1950). 59 (2): 141–146. ISSN   0022-1767. PMID   18864088.
  10. ↑ Freedberg A. S.; Ureles A. L.; Lesses M. F.; et al. (1951). "Treatment of thyroid carcinoma with radioactive iodine (I131)". Am J Med. 11 (1): 44–54. PMID   14837925 . Retrieved August 13, 2025.
  11. ↑ Ghose, T.; Norvell, S. T.; Guclu, A.; Macdonald, A. S. (1975). "Immunochemotherapy of human malignant melanoma with chlorambucil-carrying antibody". European Journal of Cancer. 11 (5): 321–326. doi:10.1016/0014-2964(75)90059-6. ISSN   0014-2964. PMID   1171762.
  12. 1 2 3 4 Fang Liang (2016). "Yàojì xué" 药剂学[Pharmaceutics]. People’s Medical Publishing House (in Chinese) (8th. ed.). ISBN   978-7-117-22380-5.
  13. ↑ Rosenberg B.; Vancamp L.; Krigas T. (1965). "Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode". Nature. 205 (4972): 698–699. Bibcode:1965Natur.205..698R. doi:10.1038/205698a0. PMID   14287410.
  14. ↑ Rosenberg B.; Vancamp L.; Grimley E. B.; Thomson A. J. (March 1967). "The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes". J. Biol. Chem. 242 (6): 1347–1352. PMID   5337590.
  15. 1 2 Lemke T. L.; Williams D. A. (2011). Foye's Principles of Medicinal Chemistry (7th ed.). Baltimore: Lippincott Williams & Wilkins. pp. 1199–1267. ISBN   978-1-609-133450.
  16. 1 2 3 4 Fang Hao (February 2016). 药物设计学 [Drug Design] (in Chinese) (Third ed.). Beijing: People's Medical Publishing House. ISBN   978-7-117-21921-1 . Retrieved August 13, 2025.
  17. ↑ Horwitz S. B.; Goldman D. (2015). "A Conversation with Susan Band Horwitz". Annual Review of Pharmacology and Toxicology. 55: 1–9. doi:10.1146/annurev-pharmtox-010814-124519. Archived from the original on 2022-03-16. Retrieved August 13, 2025.
  18. ↑ Holton, Robert A.; Somoza, Carmen; Kim, Hyeong Baik; Liang, Feng; Biediger, Ronald J.; Boatman, P. Douglas; Shindo, Mitsuru; Smith, Chase C.; Kim, Soekchan (1994-02-01). "First total synthesis of taxol. 1. Functionalization of the B ring". Journal of the American Chemical Society. 116 (4): 1597–1598. doi:10.1021/ja00083a066. ISSN   0002-7863.
  19. ↑ Buchi, G.; MacLeod, William D.; Padilla, J. (1964-10-01). "Terpenes. XIX.1 Synthesis of Patchouli Alcohol2". Journal of the American Chemical Society. 86 (20): 4438–4444. doi:10.1021/ja01074a041. ISSN   0002-7863.
  20. ↑ Büchi, G.; Erickson, R. E.; Wakabayashi, Nobel (1961-02-01). "Terpenes. XVI.1,2 Constitution of Patchouli Alcohol and Absolute Configuration of Cedrene". Journal of the American Chemical Society. 83 (4): 927–938. doi:10.1021/ja01465a042. ISSN   0002-7863.
  21. ↑ Collins Glenn (March 7, 1996). "2 Swiss Drug Giants In a Surprise Merger To Be 2d in World". New York Times. Archived from the original on 2017-08-08. Retrieved August 13, 2025.
  22. 1 2 Zhāng Jǐnghǎi (February 2016). Yàoxué fēnzǐ shēngwùxué药学分子生物学[Molecular Biology of Pharmacy] (in Chinese) (Eighth ed.). Beijing: People's Medical Publishing House. pp. 174–179. ISBN   978-7-117-22373-7.
  23. 1 2 3 4 5 Yang Baofeng; Su Dingfeng (March 2013). Yàolǐxué药理学[Pharmacology] (in Chinese) (8th ed.). Beijing: People's Medical Publishing House. pp. 438–456. ISBN   978-7-117-16975-2.
  24. 1 2 Pharmacopoeia Commission of the People’s Republic of China (August 2015). Zhōnghuá Rénmín Gònghéguó Yàodiǎn中华人民共和国药典[Pharmacopoeia of the People's Republic of China] (in Chinese) (2015 ed.). Beijing: China Medical Science Press. ISBN   978-7-5067-4439-3.
  25. ↑ Hurley, Laurence H. (2002). "DNA and its associated processes as targets for cancer therapy". Nature Reviews. Cancer. 2 (3): 188–200. doi:10.1038/nrc749. ISSN   1474-175X. PMID   11990855.
  26. ↑ Eck, Michael J.; Manley, Paul W. (2009). "The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl". Current Opinion in Cell Biology. 21 (2): 288–295. doi:10.1016/j.ceb.2009.01.014. ISSN   1879-0410. PMID   19217274.
  27. 1 2 3 4 5 Brunton L. L.; Lazo J. S. (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: The McGraw-Hill Companies Inc. pp. 1021–1404. ISBN   978-0071422802.
  28. 1 2 3 4 5 Lóu Yíjiā (February 2016). Yàowù dúlǐxué药物毒理学[Toxicology of Drugs] (in Chinese) (Fourth ed.). Beijing: People's Medical Publishing House. ISBN   978-7-117-22371-3.
  29. 1 2 3 4 Katzung B. G. (2012). Katzung's Basic and Clinical Pharmacology (12th ed.). New York: The McGraw-Hill Companies Inc. ISBN   978-0071764018.
  30. 1 2 3 4 Tán Yùzhì; Táng Shèngsōng (December 2009). Yàowù dúlǐxué, ànlì bǎn药物毒理学[Toxicology of Drugs] (in Chinese) (Case Study ed.). Beijing: Science Press. ISBN   978-7-030-26292-9.
  31. 1 2 3 4 Jin Boquan; Cao Xuetao (March 2013). Cáo Xuětāo医学免疫学 [Medical Immunology] (in Chinese) (Sixth ed.). Beijing: People's Medical Publishing House. ISBN   978-7-117-17101-4.
  32. ↑ Abraham D. J.; Rotella D. P. (2010). Burger's Medicinal Chemistry, Drug Discovery and Development (7th ed.). Hoboken: John Wiley & Sons Inc. ISBN   978-0470278154.
  33. ↑ Torchilin, Vladimir P. (2006-12-01). "Multifunctional nanocarriers". Advanced Drug Delivery Reviews. 58 (14): 1532–1555. doi:10.1016/j.addr.2006.09.009. ISSN   0169-409X. PMID   17092599.
  34. ↑ Frank Heynick (2002). Jews and Medicine: An Epic Saga. Hoboken: Ktav. pp.  354–355. ISBN   0881257737.
  35. ↑ Bangham, A. D.; Horne, R. W. (1964). "Negative Staining of Phospholipids and Their Structural Modification by Surface-Active Agents As Observed in the Electron Microscope". Journal of Molecular Biology. 8: 660–668. doi:10.1016/s0022-2836(64)80115-7. ISSN   0022-2836. PMID   14187392.
  36. ↑ Horne, R. W.; Bangham, A. D.; Whittaker, V. P. (1963-12-28). "Negatively Stained Lipoprotein Membranes". Nature. 200: 1340. doi:10.1038/2001340a0. ISSN   0028-0836. PMID   14098499.
  37. ↑ Bangham, A. D.; Horne, R. W.; Glauert, A. M.; Dingle, J. T.; Lucy, J. A. (1962-12-08). "Action of saponin on biological cell membranes". Nature. 196: 952–955. doi:10.1038/196952a0. ISSN   0028-0836. PMID   13966357.
  38. ↑ Cobleigh, Melody A.; Langmuir, Virginia K.; Sledge, George W.; Miller, Kathy D.; Haney, Latrice; Novotny, William F.; Reimann, James D.; Vassel, Amy (2003). "A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer". Seminars in Oncology. 30 (5 Suppl 16): 117–124. doi:10.1053/j.seminoncol.2003.08.013. ISSN   0093-7754. PMID   14613032.
  39. ↑ Cobleigh, Melody A.; Langmuir, Virginia K.; Sledge, George W.; Miller, Kathy D.; Haney, Latrice; Novotny, William F.; Reimann, James D.; Vassel, Amy (2003). "A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer". Seminars in Oncology. 30 (5 Suppl 16): 117–124. doi:10.1053/j.seminoncol.2003.08.013. ISSN   0093-7754. PMID   14613032.
  40. ↑ Lee J. H.; Yeo Yoon (2015-03-24). "Controlled drug release from pharmaceutical nanocarriers". Chemical Engineering Science. Pharmaceutical Particles and Processing. 125: 75–84. doi:10.1016/j.ces.2014.08.046. PMC   4322773 . PMID   25684779. Archived from the original on 2022-06-22. Retrieved August 16, 2025.
  41. ↑ Cho Kwangjae; Wang Xu; Nie Shuming; et al. (2008-03-01). "Therapeutic nanoparticles for drug delivery in cancer". Clinical Cancer Research. 14 (5): 1310–1316. doi:10.1158/1078-0432.CCR-07-1441. ISSN   1078-0432. PMID   18316549.
  42. ↑ Hait, William N. (2010). "Anticancer drug development: the grand challenges". Nature Reviews. Drug Discovery. 9 (4): 253–254. doi:10.1038/nrd3144. ISSN   1474-1784. PMID   20369394.
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