Antineoplastic drugs Basic pharmacology Typical antineoplastic

Antineoplastic drugs － Basic pharmacology － Typical antineoplastic drugs － Common toxicity and rational use Weiping Zhang, Ph. D. , MD Email: weiping 601@zju. edu. cn Dept. Pharmacology, Medical School, Zhejiang University

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

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

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

Part I basis of antineoplatics Classification Cytotoxic agents - Most typical agents Ø Alkylating agents (烷化剂 : 氮芥类等 ) Ø Antimetabolites (抗代谢物 : MTX, 5 5 -FU 等) Ø Antineoplastic antibiotics (抗肿瘤抗生素 ) Ø Antineoplastic plant drugs (抗肿瘤植物药 ) Ø Others：(其他 : 铂类配合物和门冬酰胺酶 Non-cytotoxic agents - Currently developed rapidly Ø Hormones and their antagonists(激素及其拮抗剂 ) Ø Molecular targeted agents(分子靶向药物 ) Others Ø Retinoic acid(维甲酸） Ø Arsenious acid (三氧化二砷 , As As 2 O 3 )

Part I basis of antineoplatics Classification －According to the chemical structure and/or resources Ø Antimetabolites －Cytarabine (Ara-C，阿糖胞苷）－Methotrexate (MTX, 氨甲蝶呤) Ø Antitumor antibiotics －Bleomycin （BLM，博莱霉素）－Daunorubicin （柔红霉素） Ø Alkylating agents －Cyclophosphamide（CTX，环磷酰胺）－Nitrogen mustard（NH 2，氮芥） ØPlant alkaloids （microtule inhibitor）－Vinblastin (VLB，长春碱) －Paclitaxel（taxol，紫杉醇） Ø Hormones and antagonists －Estrogens（雌激素类）－Tamoxifen（TAM，他莫昔芬） Ø Others －Cisplatin（DDP，顺铂）－Interferon（干扰素）

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

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

Part I basis of antineoplatics Classification －According to the biochemical mechanisms 1. Drugs inhibiting biosynthesis of nucleic acid Ø Ø Ø 抑制二氢叶酸还原酶: 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-C（阿糖胞苷） 2. Directly destroying DNA structure and function Ø Ø 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 ) Ø Antibiotics destroying DNA: MMC ( 丝裂霉素 C), ), BLM ( 博来霉素 ) Ø Inhibitor of DNA-topoisomerase: )topoisomerase CPT ( 喜树碱 ), VP 16 ( 依托泊甙)

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

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

Part I basis of antineoplatics Classification －According to the cell cycle 无增殖能力有增殖的潜能 Relaps e

Classes 3 Cancer chemotherapy drug 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

Classes 3 Cancer chemotherapy drug classes －According to the cell cycle

Resistance 1. Resistance of cancer chemotherapeutic drugs Ø Primary resistance (Natural resistance) －The cancer cells in G 0 phase －Malignant melanoma －Renal cell cancer －Brain cancer.

Resistance 1. Resistance of cancer chemotherapeutic drugs Ø 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 , P 450 ; (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, d. CTP , metabolize . －Micrtotubule inhibitors, P-gp －Hormones, the change of receptor numbers and affinity

Resistance 1. Resistance of cancer chemotherapeutic drugs Ø 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.

Resistance 1. Resistance of cancer chemotherapeutic drugs Ø Multidrug resistance protein 1 (MRP 1) －Belongs to the ATP-binding cassette transmembrane transporter superfamily.

Resistance Some ATP-binding cassette trans-membrane transporter superfamily Nomenclature Traditional name Full name ABCB 1 P-gp/MDR 1 Multidrug resistant gene/P-glycoprotein， ABCB 11 BSEP/SPGP Bile salt export pump/sister P-glycoprotein， ABCC 1 MRP 1 Multidrug resistance protein 1 ABCC 2 MRP 2/c. MOAT Multidrug resistance protein 2 ABCC 3 MRP 3 Multidrug resistance protein 3 ABCC 4 MRP 4 Multidrug resistance protein 4 ABCG 2 BCRP Breast cancer resistance protein

Resistance

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

Resistance P-gp (MDR) inhibitors 2007

Resistance P-gp (MDR) inhibitors • 1 st generation: some clinical using drugs with low affinity to P-gp, verapamil, amiodarone, reserpine etc. • 2 st generation: can inhibit P 450 and other transporters. Low affinity and non-specific, PSC-833 (valspodar)、 dexverapamil、Ro 11 -2933、 GF 120918 (elacridar). • 3 rd generation: selective P-gp inhibitor, XR 9576（tariquidar）、VX-710 (biricodar)、 R 101933（laniquidar）、LY 335979、GF 120918、 XR 9051、OC 144 -093、VX-710、VX-853

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

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

Alkylating agents – CH 3 Ifosfamide 异磷酰胺

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

Adenine Rang 50. 4 Cytosine Guanine

Nitrogen mustard, NH 2 Ø 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 Ø Histopatholobical findings from the victims －Low white blood cell count － Bone marrow aplasia (tissue growth failure). A soldier with mustard gas burns sustained World War I －1919 Ø 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

Cyclophosphamide, CTX Metabolism

Cyclophosphamide, CTX Ø Pharmacological property －Metabolize to alkylating; Ø 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

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

Other alkylating agents Ø 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 Ø Streptozocin （链脲霉素）－A naturally sugar-containing nitrosourea －Toxicity to pancreatic islet cell Streptozocin

Other alkylating agents （略） Procarbazine （丙卡巴肼） • Inhibit DNA, RNA and protein biosynthesis • Produces chromosome breaks • Produces azoprocarbazine and H 2 O 2 • Commnonly used in combination regimens for Hodgkin’s disease, non-Hodgkin’s lymphoma and brain tumors. • Has leukemogenic, teratogenic and mutagenic properties.

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

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.

Platinum analogs Ø Platinum analogs are inorganic metal complex, which have the similar cytotoxicity as alkylating agents. Cisplatin，DDP，顺铂 Ø Primary biding site is the N 7 position of guanine, but covalent interaction with adenine and cytosine. Ø Can also bind to –SH of proteins Ø Can synergize with certain other anticancer drugs. Carboplatin，CBP，卡铂

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

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

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

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.

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 G 2/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

Clinical uses 主要治疗鳞状细胞上皮癌 (squamous 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。

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

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 G 1 －Primarily used to inhibit transcription and DNA replication

Antitumor antibiotics inhibit DNA/RNA synthesis Ø 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.

Antimetabolites Ø Antimetabolites are structurally related to normal cellular components. Ø 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. Ø Their maximal cytotoxic effects are S-phase (and therefore cellcycle) specific. Synthesis of DNA, RNA and protein

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

Antimetabolites Folic acid DHFR FH 2 Methotrexate DHFR FH 4 Methyl-FH 4 (leucovorin) N 5 N 10 -methene-FH 4 Deoxyribonucleotides

Methotrexate Clinical uses Ø Acute leukemia in children (儿童急性白血病) Ø Chorioepithelioma（绒毛膜上皮癌） Ø 目前主张先用大剂量MTX治疗，随后用甲酰四氢叶酸作为“救援剂（rescue agents）”，可保护骨髓正常细胞，拮抗其毒性

Fluorouracil（氟尿密度，5 -Fu） Ø 5 -FU 是尿嘧啶的衍生物在尿嘧啶环第位的取代，转变为氟尿嘧啶脱氧核苷酸（ 5 F-d. UMP ） Ø 5 F-d. UMP可抑制thymidylate synthase（脱氧胸苷酸合成酶） Ø 5 F-d. UMP可转化为 5 -FUR（5 -氟尿嘧啶核苷），作为伪产物掺入RNA中，感染蛋白质合成。 Ø 用于多种实体瘤：esp消化道癌症和乳癌。 F 尿嘧啶 5 -FU

Mercaptopurine（巯嘌呤，6 -MP） Ø 6 -MP thioinosinic acid （硫代肌苷酸）， Ø 硫代肌苷酸可抑制肌苷酸转变为胸苷酸（AMP）和鸟苷酸（GMP），主要作用于S期细胞。 Ø 用于儿童急性淋巴性白血病疗效显著，但起效较慢，大剂量用于绒毛膜上皮癌。 NH 2 巯嘌呤 6 -MP

Hydroxyurea（羟基脲，HU） Ø HU 抑制nucleotide reductase （核苷酸还原酶），阻止胞苷酸（CMP）转变为退养胞苷酸（d. CMP）。 Ø 用于慢性粒细胞白血病，对转移性黑色素瘤有暂时缓解作用。 Ø 可用作同步化疗药，使细胞集中在G 1期。

Cytarabine（阿糖胞苷，Ara-C） Ø Ara-C与胞嘧啶核苷相似。主要作用于S期。 Ø 经脱氧胸苷酸激酶催化二磷酸或三磷酸胞苷抑制 DNA多聚酶。或者掺入DNA中干扰其复制。 Ø 用于成人急性粒细胞白血病和单核细胞白血病。

Topoisomerase inhibitors Ø Camptothecins (Topotecan, Irinotecan) Hydroxycamptothecin (HCPT，羟喜树碱) Topetecan（TPT，拓扑特肯） Irinotecan（CPT-11，依林特）－Derived from the camptotheca acuminata tree; －Inhibit topoisomerase I (CCNS, but S>G 1 and G 2) －Topotecan is usually a second-line drug for advanced ovarian cancer －Irinotecan is for metastatic clorectal cancer

Topoisomerase inhibitors Ø Epipodophyllotoxins (etoposide, VP 16, 依托泊苷and teniposide, VM-26，替尼泊苷) - Semisynthetic drivatives of podophyllotoxin（足叶草毒素，鬼臼毒素）, which is extracted from the mayapple root (podophyllum peltatum，盾叶鬼臼). - CCNS, more sensitive to S and G 2 phase. Inhibition of microtubule, topoisomerase II and damage DNA - Etoposide has been used for germ cell cancer, small cell and non-small cell lung cancer, Hodgkin’s and non. Hodgekin’s lymphomas and gastric cancer. - Teniposide is limited mainly to acute lymphoblastic leukemia.

Drugs inhibiting protein synthesis and functions Plant alkaloids - Vinca alkaloids （长春碱类）inhibit microtubule polymerization. - Cochicine （秋水碱类） alters the 3 D inter-microtubule instability. - Taxanes （紫杉烷类） stabilize polymerized microtubules protofilaments.

Plant alkaloids Ø Vinblastine （VLB，长春花碱） - An alkaloid derived from the periwinkle plant vinca rosea. - Disrupt assembly of microtubules. - Used for Hodgkin’s disease, non Hodgkin’s lymphomas, breast cancer and germ cell cancer. M phase Ø Vincristine（VCR，长春新碱） - Effective when combined with prednisone for acute lymphoblastic leukemia in children and various hematologic malignancies. Ø Vinorelbine （NVB，长春瑞滨） - New, effective for small cell lung cancer

Plant alkaloids Ø Colchicine （略） - Derived from genus Colchicum - Microtubules were identified as a cellular component based on their ability to bind colchicine. - Disrupting the 3 D structure of tubublin interactions - Originally used for rheumatic complaints and gout disease (for cathartic and emetic). - Its anti-cancer therapy is inhibited by its toxicity.

Plant alkaloids Ø Taxanes (Paclitaxel，紫杉醇) - An alkaloid ester derived from the pacific yew, the European yew and Chinese yew; - Enhance and stable tubulin polymerization; - Used on broad range of solid tumors, late phase ovary cancer, metastatic breast cancer. - Metabolize by liver P 450 and eliminate with feces - Novel albumin-bound paclitaxel formulation (Abraxane) Less hypersensitivity

Hormonal agents Ø Mechanisms of action －Intracellular cascade of events • Apoptosis • Paracrine vs autocrine mechanisms • HPA axon －Activate/block the receptors －palliative therapy （姑息性治疗）

Hormonal agents Ø Estrogen （雌激素） & androgen（雄激素） inhibitors - Tamoxifen (他莫昔芬，a partial agonist-inhibitor of estrogen receptor), for early-stage and metastatic breast cancer. Chemopreventive for women at high risk for breast cancer. - Flutamide（氟他米特） and bicalutamide（比卡鲁胺）, nonsteroidal antiandrogen agents, for early-stage prostate cancer and in the setting of metastatic prostate cancer.

Hormonal agents Ø Estrogen （雌激素） & androgen（雄激素） - Diethylstilbestrol (已烯雌酚), inhibit HPA and thus decrease the release of testosterone. Directly antagonize testosterone - Methyltestosterone（二甲基睾丸酮）, testosterone propionate（丙酸睾丸酮）, and fluoxymesterone（氟羟甲酮）， inhibit HPA and thus decrease the release of estradrone. Directly antagonize estradrone Male hormones

Hormonal agents Ø Gonadotropin-releasing hormone （Gn. RH） agonists - Leuprolide（醋酸亮丙瑞林） and goserelin（戈舍瑞林） - Inhibition of the release of LH and FSH. - Results in castration levels of testosterone in men. - For advanced prostate cancer and for adjuvant therapy of early-stage prostate cancer. - Main adverse effects include hot flushes, impotence and gynecomastia.

Hormonal agents Cytochrome P 450 superfamily Aromatase inhibitors ×

Hormonal agents Ø Aromatase inhibitors Aminoglutethimide（氨鲁米特）, a nonsteroidal inhibitor of corticosteroid synthesis - Inhibit adrenal and extra-adrenal synthesis of estrone and estradiol. Increase the metabolize of estrone. - Inhibit P 450 and block the conversion of cholesterol to pregnenolon. Anastrozole（阿那曲唑）, Letrozole（来曲唑）, Exemestane （依西美坦） - Inhibitors of aromatase - Had no effects on adrenal glucocorticoid or mineralocorticoid synthesis - Anastrozole, Letrozole are among the first-line treatment of postmenopausal women with metastatic breast cancer.

Hormonal agents Ø Corticosterioids Prednisone（泼尼松） and prednisonlone （泼尼松龙） - Inducing apoptosis of T (low concentration) and B lymphocytes (high concentration) - Potently immunosuppressive - Used in the regimen for lymphocytolytic - Ineffective for the solid tumor

Interferon Ø Include , , -interferon Ø Kill cancer cells Ø Probably through the stimulation of NK cell Ø -INF can activate macrophage cell Ø Effective in hairy-cell leukemia（毛细胞白血病）， squamous cell carcinoma（磷状上皮癌）, melanoma（黑色素瘤） and multiple myeloma（多发性骨髓瘤）

Novel chemotherapies in oncology ü Differentiation inducer ü Proteasome inhibitor ü TRAIL receptor signal pathway inducer ü PI 3 K-AKT-m. TOR signal pathway inhibitor ü MDM 2–p 53 inhibitor ü Hypoxic selective agents ü Tumor metastasis inhibitor http: //clinicaltrials. gov/ ü Reversal agents of chemoresistance ü Vaccines ü Adjuvant interferon

Novel chemotherapies in oncology （略） Ø Retinoic acid derivatives - Induction of differentiation, induction of clinical remission - All-trans-retinoic acid (tretinoin), effective for acute promyelocytic leukemia, but result in a number of serious adverse events. Ø Arsenic trioxide - Functions by inducing differentiation through degratdation of the chimeric PML/RAR- protein. Also it induce cell apoptosis.

Novel chemotherapies in oncology （略） Ø Imatinib - Inhibitor of the tyrosine kinase domain of the Bcr-Abk oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. - First-line for the treatment of chronic myelogenous leukemia, blast crisis. Second-line for chronic phase CM that has progressed on prior INF- therapy. Ø Growth factor receptor inhibitors - Cetuximab, a chimeric monoclonal antibody against the extracellular domain of EGFR. - Gefitinib & Erlotinib, small molecule inhibitor of the tyrosine kinase domain associated with the EGFR. - Bevacizumab, recombinant humanized monoclonal antibody that targets all forms of VEGF-A.

Common toxicity and rational use Long-term toxicity Ø Secondly malignant tumor- alkylating agents －Mutagenesis (致突变) －Carcinogenicity (致癌) Ø Sterility (不育) teratogenecity (致畸性) －Man: azoospermia(无精), impotence（性无能）－Woman: ovary dysfunction, amenorrhea（闭经）, abortion（流产） or abnormity（畸胎）

Short-term toxicity Common toxicity（共同毒性） Ø Target to the cells undergoing rapid proliferation: buccal mucosa, bone marrow, gastrointestinal (GI) mucosa, hair cells. Ø Myelosuppression（WBC, platelet, RBC） Ø GI responses: severe vomiting, stomatitis Ø Hair cells: alopecia Dose-limiting

Short-term toxicity --- Common Comparison of myelosuppression potential Cancer treatment support ü Psychological support ü Physical support

Short-term toxicity --- Special Ø Immunosuppression (infections) Ø Skin (extravasation, photosensitivity) Ø Liver (veno-occlusive disease, hepatocellular damage) Ø Pancrease (pancreatitis) Ø Lung (pulmonary fibrosis) Ø Heart (congestive heart failure, arrhythmias) Ø Genitourinary (cystitis, renal failure) Ø Nervous system (peripheral neuropathy, autonomic neuropathy, encephalopathy) Ø Gonadal function (azoospermia, impotence, amenorrhea) Ø Miscellaneous: electrolyte problems, diabetes, endocrine failure, pathologic fractures, hemolytic anemia, growth suppression, and others.

Short-term toxicity --- Alkylating agents Mechlorethamine（氮芥） Ø Severe vomiting (CNS) and myelosuppression Ø Immunosuppression virus infection Ø Skin (extravasation) can be treated with sodium thiosulfate (硫代硫酸钠) Cyclophosphamide （环磷酰胺） Ifosfamide（异磷酰胺） Ø Severe vomiting, alopecia and myelosuppression Ø Cystitis（膀胱炎） MESNA (巯乙磺酸钠) Ø Neurotoxicity High dosage Carmustine（卡莫司汀）Lomustine（洛莫司汀） Ø Myelosuppression 骨髓再生性障碍 Ø Nephrotoxicity and lung fibrosis

Short-term toxicity --- Platinum complexes Cisplatin （顺铂） Ø Severe and lasting vomiting Ø Nephrotoxicity and electrocyte disturbances rehydration and diuresis Ø Ototoxicity （耳毒性） Carboplatin（卡铂） Ø Severe and lasting vomiting Ø Dose-dependent myelosuppression

Short-term toxicity --- Antibiotics Mitomycin （丝裂霉素） Ø Severe and lasting myelosuppression Ø GI response and local injection site response Bleomycin（博莱霉素） Ø Skin toxicity and alopecia Ø Lethal lung fibrosis Actinomycin D（放线菌素D） Ø Dose-dependent myelosuppression Ø Immunodepression Ø Skin (extravasation can induce necrosis, radiosensitivity induce local inflammation) Doxorubicin（多柔比星）Daunorubicin（柔红霉素） Ø Irreversible cardiac toxicity Ø Sever alopecia

Short-term toxicity --- Antimetabolites Methotrexate （甲胺喋呤） Ø Vomiting, stomatitis, alopecia and myelosuppression; Ø Nephrotoxicity at high dosage Ø Hepatic fibrosis Ø Abnormal Ø reversible lung toxicity Ø All can be lightened by tetrahydrofolic acid 6 -thiopurines（6 -巯嘌呤） Ø Myelosuppression

Short-term toxicity --- Antimetabolites 5 -Fluorouracil （5 -Fu, 5氟尿嘧啶） Ø Vomiting, diarrhea and alopecia; Ø Sever stomatitis (口腔炎) and myelosuppression (at high dose) Ø Skin, hand-foot syndrome Cytarabine（阿糖胞苷） Ø Sever vomiting, diarrhea and myelosuppression Ø CNS response at high dose or intra-vertebral cannal infusion

Short-term toxicity --- Topoisomerase inhibitor Camptothecins （喜树碱） Ø Vomiting, alopecia and myelosuppression; Etoposide（依托泊苷） Ø Myelosuppression Ø Hypotension if the infusion is too fast

Short-term toxicity --- Plant alkaloids Vinblastin （长春花碱）and Vincristin（长春新碱） Ø Skin extravasation and induce phlebitis （静脉炎）and cellulitis（蜂窝组织炎） Ø Vomiting, diarrhea and alopecia Ø Vinblastin has severe myelosuppression Ø Vincristin and induce peripheral neuronal toxicity, paraesthesia（感觉异常）areflexia（反射消失）ataxia（共济失调） Taxanes（紫杉醇） Ø Severe allergy Ø Granulocytopenia（粒细胞减少）

Short-term toxicity --- Hormonal agents Tamoxifen （他莫昔芬） Ø Can decrease LDL and protect cardiovascular system Ø Induce hypercalcemia （高血钙）and endometrial cancer（子宫内膜癌） Estragen（雌激素） Ø Azoospermia, impotence Corticosteroids（糖皮质激素）

Minimizing the toxicity Ø Decrease the dose; Ø Local infusion; Ø Follow-up; Ø Prevention, e. g. tetrahydrofolic acid Ø Physical and psychological support Ø Targeting

Rational use of antineoplastic agents (1) Goals for chemotherapy Ø Ø Complete Remission Partial Remission Stable Disease Progressive Disease CURE ------ LONG-TERM, DISEASE-FREE SURVIVAL.

(2) Important of neoplastic cell burden

(3) Methods of treatment Combination chemotherapy is more effective than single-drug in most cancers for which chemotherapy is effective Advantages of Combination chemotherapy : (1) Provide maximal cell kill within the range of tolerated toxicity (2) Effective against a broader range of cell lines in the heterogeneous tumor population (3) Slow or prevent the development of resistant cell lines.

(3) Methods of treatment Mechanisms under combination chemotherapy : (1) Recruitment and synchronization 募集和同步化 (2) Synergistic mechanisms 协同机制 (3) Non-overlapping toxicities. 毒性反应无重叠

(3) Methods of treatment Treatment protocols: (1) Different treatment protocols have been developed for various particular neuoplastic state. (2) Acronym: for example POMP is a common regimen for the treatment of acute lymphocytic leukemia(ALL) consists of Prednisone, Oncovin (vincristine), Methotrexate and Purinethol.