Antineoplastic drugs

1. Antineoplastic drugs － Basic pharmacology － Typical antineoplastic drugs － Common toxicity and rational use Weiping Zhang, Ph.D., MDEmail: weiping601@zju.edu.cn Dept. Pharmacology, Medical School, Zhejiang University

2. Treatment of Cancer • Chemotherapy(disseminated neoplams include germ cell caner, non-Hodgkin’s lymphoma, Hodgkin’s disease, choriocarcinoma, leukemia etc) • Radiation therapy • Surgery • Adjuvant therapy, include temporary improvement of the symptoms and enhancement in the overall quality of life. • Physical and psychological support

3. Treatment of Cancer Hematologic malignancies Solid tumor • Grow fast • －Inhibit proliferation • －kill • －inhibit angiogenesis • Low-differentiation • －induce

4. Palliative chemotherapy 姑息性化疗 Curative chemotherapy 治疗性化疗

5. Part I basis of antineoplatics Classification • Cytotoxic agents - Most typical agents • Alkylating agents (烷化剂 : 氮芥类等 ) • Antimetabolites (抗代谢物 : MTX, 5 5-FU 等) • Antineoplastic antibiotics (抗肿瘤抗生素 ) • Antineoplastic plant drugs (抗肿瘤植物药 ) • Others：(其他 : 铂类配合物和门冬酰胺酶 • Non-cytotoxic agents - Currently developed rapidly • Hormones and their antagonists(激素及其拮抗剂 ) • Molecular targeted agents(分子靶向药物 ) • Others • Retinoic acid(维甲酸） • Arsenious acid (三氧化二砷 , As As2 O3 )

6. Part I basis of antineoplatics Classification －According to the chemical structure and/or resources • Plant alkaloids （microtule inhibitor） －Vinblastin (VLB，长春碱) －Paclitaxel（taxol，紫杉醇） • Hormones and antagonists －Estrogens（雌激素类） －Tamoxifen（TAM，他莫昔芬） • Others －Cisplatin（DDP，顺铂） －Interferon（干扰素） • Antimetabolites －Cytarabine (Ara-C，阿糖胞苷） －Methotrexate (MTX, 氨甲蝶呤) • Antitumor antibiotics －Bleomycin （BLM，博莱霉素） －Daunorubicin （柔红霉素） • Alkylating agents －Cyclophosphamide（CTX，环 磷酰胺） －Nitrogen mustard（NH2，氮芥）

7. Part I basis of antineoplatics Classification －According to the biochemical mechanisms (1) Drugs inhibiting biosynthesis of nucleic acid (2) Drugs directly destroying DNA structure and function (3) Drugs interfering transcript process and inhibiting RNA synthesis (4) Drugs interfering protein synthesis and function

8. Part I basis of antineoplatics Classification －According to the biochemical mechanisms

9. Part I basis of antineoplatics Classification －According to the biochemical mechanisms • 1. Drugs inhibiting biosynthesis of nucleic acid • 抑制二氢叶酸还原酶: MTX MTX（甲氨蝶呤 ） • 抑制胸苷酸合成酶而阻止胸苷酸合成: 5-FU FU（氟尿嘧啶 ） • 阻止嘌呤类核苷酸合成: 6-MP MP（巯嘌呤 ） • 抑制核苷酸还原酶: HU HU（羟基脲 ） • 抑制DNA 多聚酶 : Ara Ara-C（阿糖胞苷 ） • 2. Directly destroying DNA structure and function • Alkylating agents ( 烷化剂 ): CTX ( 环磷酰胺 ) • Platinum coordination complexes destroying DNA ( 破坏 DNA 的铂类配合物 ):DDP ( 顺铂 ), CBP ( 卡铂 ) • Antibiotics destroying DNA:MMC ( 丝裂霉素 C), ),BLM ( 博来霉素 ) • Inhibitor of DNA-topoisomerase: )topoisomerase CPT ( 喜树碱 ), VP16 ( 依托泊甙)

10. Part I basis of antineoplatics Classification －According to the biochemical mechanisms • 3. Interfering transcript process and inhibiting RNA synthesis • Antitumor antibiotics: DACT（放线菌素D）、ADM（多柔比星）、DNR（柔红霉素） • 4. Interfering protein synthesis and function • Affecting the formation of spindle fibers: Vinca alkaloids ( 长春碱类 ）, VLB VLB（长春碱 ）, VCR , VCR（长春新碱 ） • Interfering the function of nucleoprotein: Harringtonine(三尖杉酯碱 ) • Interfering the supply of amino acid: L-Asparaginase (L-门冬酰胺酶 )

11. Part I basis of antineoplatics Classification －According to the biochemical mechanisms Non-cytotoxic antineoplastics • Hormones (肾上腺皮质激素、雌激素、雄激素) • Signal transduction inhibitors (various pathways) • Anti-angiogenic agents • Monoclonal antibodies • Differentiation inducers • Tumor radiosensitizing and normal tissue radioprotecting drugs • Cytoprotective agents • Biologic response modifiers

12. Part I basis of antineoplatics Relapse Classification －According to the cell cycle 无增殖能力 有增殖的潜能

13. Classes 3 Cancer chemotherapydrug classes －According to the cell cycle • Information to the mode of action, indication and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs. • CCS drugs are more sensitive to hematologic malignancies and in solid tumors in which cells proliferate very fast. • CCNS drugs are very useful in both low and high growth tumors

14. Classes 3 Cancer chemotherapydrug classes －According to the cell cycle

16. Resistance 1. Resistance of cancer chemotherapeutic drugs • Primary resistance (Natural resistance) －The cancer cells in G0 phase －Malignant melanoma －Renal cell cancer －Brain cancer.

17. Resistance 1. Resistance of cancer chemotherapeutic drugs • Acquired resistance due to the mutation, decreasing or increasing the expression of one or more specific genes. Reduce intracelluar drug concentration or alter the target. －Alkylating agents: DNA repair , drug influx , binding with GSH  －Antitumor antibiotics, (1) actinomycin D and anthracyclines, P-gp expression , topoisomerase II , P450 ; (2) Bleomycin and mitomycin, e-flux , GSH-S-transferase . －Antimetabolites, (1) methotrexate, DHFR , the affinity to DHFR ; influx ; (2) 6-thiopurines, HGPRT , de-phosphate , metabolize ; (3) 5-Fu, activation , ribonucleotide synthesis ，metabolize ; (4) Cytarabine, transport , phosphorylase change, dCTP , metabolize . －Micrtotubule inhibitors, P-gp  －Hormones, the change of receptor numbers and affinity

18. Resistance 1. Resistance of cancer chemotherapeutic drugs • Properties of acquired resistance －High lipid soluble drugs －Influx cell through passive transport －The accumulation in resistant cells is fewer than it in insensitive cells －Most with P-gp expression.

19. Resistance 1. Resistance of cancer chemotherapeutic drugs • Multidrug resistance protein 1 (MRP1) －Belongs to the ATP-binding cassette trans-membrane transporter superfamily.

20. Resistance Some ATP-binding cassette trans-membrane transporter superfamily

21. Resistance

22. Resistance P-glycoprotein (MDR) The strategy to enhance the effects of cancer chemotherapy based on P-gp (MDR) inhibitors

23. Resistance P-gp (MDR) inhibitors 2007

24. Resistance P-gp (MDR) inhibitors • 1st generation:some clinical using drugs with low affinity to P-gp, verapamil, amiodarone, reserpine etc. • 2st generation:can inhibit P450 and other transporters. Low affinity and non-specific, PSC-833 (valspodar)、dexverapamil、Ro11-2933、GF120918 (elacridar). • 3rd generation: selective P-gp inhibitor, XR9576（tariquidar）、VX-710 (biricodar)、R101933（laniquidar）、LY335979、GF120918、XR9051、OC144-093、VX-710、VX-853

25. Resistance P-gp knockout and inhibitor can increase the intracaranal concentration and therapeutic effect of cancer chemotherapy drugs

26. Typical antineoplastic drugs Basic pharmacology of cancer chemotherapeutic drugs Alkylating agents 1. DNA damaging agents 1.1 Alkylating agents 1.2 Platinum complexes 1.3 Antitumor antibiotics

27. Ifosfamide 异磷酰胺 Alkylating agents – CH3

28. Alkylating agents －Mechanisms on DNA damage • Sulfhydryl －SH • Amino acid －N • Hydroxyl －OH • Carboxyl －COOH • Phosphate －Pi Guanine 鸟嘌呤

29. Adenine Rang 50.4 Cytosine Guanine

30. Nitrogen mustard, NH2 • The use of nitrogen mustard start from chemical warfare • －mustard gas (芥子气) • －blister gas （糜烂性毒气，起泡剂） • －Pure: colorless and smell less • －Chemical weapon: brown and smell • like mustard, garlic and horseradish • －1917 • Histopatholobical findings from the victims • －Low white blood cell count • － Bone marrow aplasia (tissue growth failure). • －1919 A soldier with mustard gas burns sustained World War I • Clinical property • －Hodgkin‘s disease 等恶性淋巴瘤（治疗头颈部肿瘤 , 用区域动脉内 • 给药 或者 半身化疗 压迫主 动脉阻断下半身循环 , 可以提高肿瘤局部 • 的药物浓度和减 少全身毒性 • －High efficiency and fast effect

31. Cyclophosphamide, CTX Metabolism

32. Cyclophosphamide, CTX • Pharmacological property －Metabolize to alkylating; • Clinical property －Broad spectrum; －One of the most widely used alkylating agent; －Oral route is common; －Very sensitive to malignant lymphoma －Cross-resistant with other alkylating agents

33. Ifosfamide 异磷酰胺 Cyclophosphamide, CTX Ifosfamide （异磷酰胺） －Closely related to CTX －Higher response rate

34. Other alkylating agents • Carmustine（卡莫司汀） Lomustine （洛莫司汀） －Inhibit DNA replication, －Highly lipid soluble，esp. for brain cancer －Carmustine only for iv injection －lomustine can be orally taken • Streptozocin （链脲霉素） －A naturally sugar-containing nitrosourea －Toxicity to pancreatic islet  cell Streptozocin

35. Other alkylating agents （略） Procarbazine （丙卡巴肼） • Inhibit DNA, RNA and protein biosynthesis • Produces chromosome breaks • Produces azoprocarbazine and H2O2 • Commnonly used in combination regimens for Hodgkin’s disease, non-Hodgkin’s lymphoma and brain tumors. • Has leukemogenic, teratogenic and mutagenic properties.

36. Other alkylating agents （略） Dacarbazine （达卡吧嗪） • By oxidative N-demethylation dacarbazien can be metabolized to monomethyl derivative and then decomposes to 5-aminoimidazole-4-carboxamide (excreted in the urine) and diazomethane. • Diazomethane generates methyl carbonium ion (cytotoxic species) • Commnonly used in melanoma, Hodgkin’s disease and soft tissue sarcomas

37. Other alkylating agents （略） Altretamine（六甲密胺） • Structurally similar to triethylenemelanime. • Insoluble and available only in oral form. • Biotransformed into pentamethylmelamine and tetramethylmelamine metabolites. • Used in ovarian cancer patient • Beside the usual toxicity, neurotoxicity in the from of somnolence, mood changes and peripheral neuropathy is also observed.

38. Platinum analogs • Platinum analogs are inorganic metal complex, which have the similar cytotoxicity as alkylating agents. • Primary biding site is the N7 position of guanine, but covalent interaction with adenine and cytosine. • Can also bind to –SH of proteins • Can synergize with certain other anticancer drugs. Cisplatin，DDP，顺铂 Carboplatin，CBP，卡铂

39. Platinum analogs • Broad range of solid tumors, non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer and genitourinary cancer. • The effect of CBP is stronger than DDP. • DDP is too toxic, thus developed CBP Cisplatin，DDP，顺铂 Carboplatin，CBP，卡铂

40. Platinum analogs • Oxaliplatin is relative new (proved by FDA in 2002, but has never been proved to be more effective Oxaliplatin, 奥沙利铂

41. Antitumor antibiotics damage DNA • Came from the screening of microbial products • Products of various strains of the soil microbe streptomyces. • Include mitomycin, bleomycin. • And Actinomycin D, Anthracyclines

42. Antitumor antibiotics damage DNA Mitomycin (丝裂霉素，mitomycin C) －MMC 结构中有 乙撑亚 胺基团和,氨甲酰酯基团有烷化作用. －A special use is in the intravesical treatment of superficial bladder cancer. －Hypoxic tumor stem cells of solid tumors are more sensitive. －The best available drug for use in combination with radiation therapy to hypoxic tumor cells.

43. Antitumor antibiotics damage DNA Bleomycin (博莱霉素) －A small glyco-peptide containing DNA binding region and an iron/copper-binding domain. －Produce free radicals and breaks DNA. －A cell cycle-specific drug that causes G2/M arrest （someone refers to a CCNS drug）. －More sensitive to squamous cell carcinoma （磷状上皮癌） －Can be used on malignant lymphoma

44. Clinical uses 主要治疗 鳞状细胞上皮癌 (squamous epithelioma epithelioma), 包括 头部 , 颈部 , 口腔 ,食 管, 阴茎 , 外阴和宫颈的鳞状细胞上皮癌。Adverse reaction 主要是肺纤维化，与使用的累积剂量有 密切关系，对骨髓和免疫系统的抑制较 轻, 胃肠道反应也不严重。

45. Basic pharm. 2 Basic pharmacology of cancer chemotherapeutic drugs Antimetabolites 2. Inhibitors of DNA/RNA synthesis and integrity 2.1 Antitumor antibiotics 2.2 Antimetabolites/Folate pathway inhibitors 2.3 Topoisomerase inhibitors

46. Antitumor antibiotics inhibit DNA/RNA synthesis Actinomycin D (DACT, 放线菌素D) －Actinomycin is redirected from dactinomycin（更生霉素） －Inhibit DNA-dependent RNA polymerase －Stable topoisomerase II and DNA complex －Narrow, highly toxic. －主要治疗 恶性葡萄胎，绒毛膜上皮癌，淋巴瘤和肾母细胞瘤，横纹肌肉瘤及神经母细胞瘤等. －CCNS, but more sensitive to G1 －Primarily used to inhibit transcription and DNA replication

47. Antitumor antibiotics inhibit DNA/RNA synthesis • Anthracyclines (蒽环类，doxorubicin，多柔比星, daunorubicin,柔红霉素,idarubicin，依达比星 and epirubicin，表柔比星) －One of the most widely used cytotoxic anticancer drugs. －Mechanism including (1) inhibition of topoisomerase II; (2) high-affinity biding to DNA and block the synthesis of DNA and RNA; (3) binding to cellular membranes to alter fluidity and ion transport; (4) generate semiquinone free radicals and oxygen free radicals  cytotoxicity and cardiotoxicity. －Usually administered on every-3-week schedule or longer.

48. Antimetabolites • Antimetabolites are structurally related to normal cellular components. • They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their syntheisis or by competing with them in DNA or RNA synthesis. • Their maximal cytotoxic effects are S-phase (and therefore cell-cycle) specific. Synthesis of DNA, RNA and protein

49. Antimetabolites • DHFR inhibitors Methotrexate（氨甲喋呤） Sulfonamides（磺胺类药物） • Purine antagonists 6-thiopurines (6-MP, 6-TG，巯嘌呤) • Pyrimidine antagonists 5-fluorouracil (5-FU，5-氟尿嘧啶) • Ribonucleotide reductase inhibitor Hydroxycarbamide (HU，羟基脲） • DNA polymerase inhibitor Cytarabine（Ara-C，阿糖胞苷） • Inhibit protein synthesis Asparaginase (门冬酰胺酶)

50. Antimetabolites Folic acid DHFR FH2 Methotrexate DHFR FH4 Methyl-FH4 (leucovorin) N5N10-methene-FH4 Deoxyribonucleotides