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Antineoplastic drugs - Basic pharmacology - Typical antineoplastic drugs - Common toxicity and rational use Weiping Zhang, Ph.D., MD Email: [email protected] Dept. Pharmacology, Medical School, Zhejiang University 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 Treatment of Cancer Hematologic malignancies Solid tumor Low-differentiation -induce 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 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 ) Part I basis of antineoplatics Classification -According to the chemical structure and/or resources 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) 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) 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 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) 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) 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 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 Primary resistance (Natural resistance) -The cancer cells in G0 phase -Malignant melanoma -Renal cell cancer -Brain cancer. 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 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. Resistance 1. Resistance of cancer chemotherapeutic drugs Multidrug resistance protein 1 (MRP1) -Belongs to the ATP-binding cassette transmembrane transporter superfamily. Resistance Some ATP-binding cassette trans-membrane transporter superfamily Nomenclature Traditional name Full name ABCB1 P-gp/MDR1 Multidrug resistant gene/P-glycoprotein, ABCB11 BSEP/SPGP Bile salt export pump/sister P-glycoprotein, ABCC1 MRP1 Multidrug resistance protein 1 ABCC2 MRP2/cMOAT Multidrug resistance protein 2 ABCC3 MRP3 Multidrug resistance protein 3 ABCC4 MRP4 Multidrug resistance protein 4 ABCG2 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 • 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, PSC833 (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 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 – CH3 Ifosfamide 异磷酰胺 Alkylating agents -Mechanisms on DNA damage Sulfhydryl -SH Amino acid -N Hydroxyl -OH Carboxyl -COOH Phosphate -Pi Guanine 鸟嘌呤 Adenine Rang 50.4 Cytosine Guanine 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). A soldier with mustard gas burns sustained World War I -1919 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 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 Cyclophosphamide, CTX Ifosfamide (异磷酰胺) -Closely related to CTX -Higher response rate Ifosfamide 异磷酰胺 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 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. 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 Platinum analogs are inorganic metal complex, which have the similar cytotoxicity as alkylating agents. Cisplatin,DDP,顺铂 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. Carboplatin,CBP,卡铂 Platinum analogs Cisplatin,DDP,顺铂 Broad range of solid tumors, nonsmall 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 Carboplatin,CBP,卡铂 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 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 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 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 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。 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 G1 -Primarily used to inhibit transcription and DNA replication 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. 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 cellcycle) specific. Synthesis of DNA, RNA and protein 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) Antimetabolites Folic acid DHFR FH2 Methotrexate DHFR FH4 Methyl-FH4 (leucovorin) N5N10-methene-FH4 Deoxyribonucleotides Methotrexate Clinical uses Acute leukemia in children (儿童急性白血病) Chorioepithelioma(绒毛膜上皮癌) 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) 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( 5F-dUMP ) 5F-dUMP可抑制thymidylate synthase(脱氧胸苷酸合成酶) 5F-dUMP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。 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) 6-MP thioinosinic acid (硫代肌苷酸), 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。 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。 NH2 巯嘌呤 6-MP Hydroxyurea(羟基脲,HU) 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(dCMP)。 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。 可用作同步化疗药,使细胞集中在G1期。 Cytarabine(阿糖胞苷,Ara-C) Ara-C与胞嘧啶核苷相似。主要作用于S期。 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。 用于成人急性粒细胞白血病和单核细胞白血病。 Topoisomerase inhibitors 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>G1 and G2) -Topotecan is usually a second-line drug for advanced ovarian cancer -Irinotecan is for metastatic clorectal cancer Topoisomerase inhibitors Epipodophyllotoxins (etoposide, VP16, 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 G2 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 nonHodgekin’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 3D inter-microtubule instability. - Taxanes (紫杉烷类) stabilize polymerized microtubules protofilaments. Plant alkaloids 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 Vincristine(VCR,长春新碱) - Effective when combined with prednisone for acute lymphoblastic leukemia in children and various hematologic malignancies. Vinorelbine (NVB,长春瑞滨) - New, effective for small cell lung cancer Plant alkaloids Colchicine (略) - Derived from genus Colchicum - Microtubules were identified as a cellular component based on their ability to bind colchicine. - Disrupting the 3D 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 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 P450 and eliminate with feces - Novel albumin-bound paclitaxel formulation (Abraxane) Less hypersensitivity Hormonal agents 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 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 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 Gonadotropin-releasing hormone (GnRH) 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 P450 superfamily Aromatase inhibitors × Hormonal agents 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 P450 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 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 Include , , -interferon Kill cancer cells Probably through the stimulation of NK cell -INF can activate macrophage cell 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 http://clinicaltrials.gov/ Differentiation inducer Proteasome inhibitor TRAIL receptor signal pathway inducer PI3K-AKT-mTOR signal pathway inhibitor MDM2–p53 inhibitor Hypoxic selective agents Tumor metastasis inhibitor Reversal agents of chemoresistance Vaccines Adjuvant interferon Novel chemotherapies in oncology (略) 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. Arsenic trioxide - Functions by inducing differentiation through degratdation of the chimeric PML/RAR- protein. Also it induce cell apoptosis. Novel chemotherapies in oncology (略) 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. 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 Secondly malignant tumor- alkylating agents -Mutagenesis (致突变) -Carcinogenicity (致癌) 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) Target to the cells undergoing rapid proliferation: buccal mucosa, bone marrow, gastrointestinal (GI) mucosa, hair cells. Myelosuppression(WBC, platelet, RBC) GI responses: severe vomiting, stomatitis Hair cells: alopecia Dose-limiting Short-term toxicity --- Common Comparison of myelosuppression potential Cancer treatment support Psychological support Physical support Short-term toxicity --- Special Immunosuppression (infections) Skin (extravasation, photosensitivity) Liver (veno-occlusive disease, hepatocellular damage) Pancrease (pancreatitis) Lung (pulmonary fibrosis) Heart (congestive heart failure, arrhythmias) Genitourinary (cystitis, renal failure) Nervous system (peripheral neuropathy, autonomic neuropathy, encephalopathy) Gonadal function (azoospermia, impotence, amenorrhea) Miscellaneous: electrolyte problems, diabetes, endocrine failure, pathologic fractures, hemolytic anemia, growth suppression, and others. Short-term toxicity --- Alkylating agents Mechlorethamine(氮芥) Severe vomiting (CNS) and myelosuppression Immunosuppression virus infection Skin (extravasation) can be treated with sodium thiosulfate (硫代硫 酸钠) Cyclophosphamide (环磷酰胺) Ifosfamide(异磷酰胺) Severe vomiting, alopecia and myelosuppression Cystitis(膀胱炎) MESNA (巯乙磺酸钠) Neurotoxicity High dosage Carmustine(卡莫司汀)Lomustine(洛莫司汀) Myelosuppression 骨髓再生性障碍 Nephrotoxicity and lung fibrosis Short-term toxicity --- Platinum complexes Cisplatin (顺铂) Severe and lasting vomiting Nephrotoxicity and electrocyte disturbances rehydration and diuresis Ototoxicity (耳毒性) Carboplatin(卡铂) Severe and lasting vomiting Dose-dependent myelosuppression Short-term toxicity --- Antibiotics Mitomycin (丝裂霉素) Severe and lasting myelosuppression GI response and local injection site response Bleomycin(博莱霉素) Skin toxicity and alopecia Lethal lung fibrosis Actinomycin D(放线菌素D) Dose-dependent myelosuppression Immunodepression Skin (extravasation can induce necrosis, radiosensitivity induce local inflammation) Doxorubicin(多柔比星)Daunorubicin(柔红霉素) Irreversible cardiac toxicity Sever alopecia Short-term toxicity --- Antimetabolites Methotrexate (甲胺喋呤) Vomiting, stomatitis, alopecia and myelosuppression; Nephrotoxicity at high dosage Hepatic fibrosis Abnormal reversible lung toxicity All can be lightened by tetrahydrofolic acid 6-thiopurines(6-巯嘌呤) Myelosuppression Short-term toxicity --- Antimetabolites 5-Fluorouracil (5-Fu, 5氟尿嘧啶) Vomiting, diarrhea and alopecia; Sever stomatitis (口腔炎) and myelosuppression (at high dose) Skin, hand-foot syndrome Cytarabine(阿糖胞苷) Sever vomiting, diarrhea and myelosuppression CNS response at high dose or intra-vertebral cannal infusion Short-term toxicity --- Topoisomerase inhibitor Camptothecins (喜树碱) Vomiting, alopecia and myelosuppression; Etoposide(依托泊苷) Myelosuppression Hypotension if the infusion is too fast Short-term toxicity --- Plant alkaloids Vinblastin (长春花碱)and Vincristin(长春新碱) Skin extravasation and induce phlebitis (静脉炎)and cellulitis ( 蜂窝组织炎) Vomiting, diarrhea and alopecia Vinblastin has severe myelosuppression 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) Severe allergy Granulocytopenia(粒细胞减少) Short-term toxicity --- Hormonal agents Tamoxifen (他莫昔芬) Can decrease LDL and protect cardiovascular system Induce hypercalcemia (高血钙)and endometrial cancer(子宫内膜 癌) Estragen(雌激素) Azoospermia, impotence Corticosteroids(糖皮质激素) Minimizing the toxicity Decrease the dose; Local infusion; Follow-up; Prevention, e.g. tetrahydrofolic acid Physical and psychological support Targeting Rational use of antineoplastic agents (1) Goals for chemotherapy 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.