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1、Cancer TherapyThe specific approach used to treat cancer depends upon the specific type, location, and stage of the cancerFundamental techniques available to treat cancer: Surgery Radiation therapy Immunologic treatment Chemical based approachesGenerally, each has its own merits, and a combination o
2、f these methods is usedSurgery: The cancer must still be in the primary tumor stageA high degree of confidence that the entire tumor can be excised Removing the tumor without causing significant damage to vital organsRadiation therapy: is used to shrink or destroy tumors This approach requires that
3、the tumor be localized X-ray radiation is used by focusing an X-ray beam on the tumorImmunologic Therapy: Utilize the immune system to eradicate the cancerThis methodology attempts to boost the level of T-cell and B-cell The major role of T-cell is to destroy foreign cells, including malignant cells
4、 B-cell is produced in the bone marrow and lymph nodes, make antibodies in response to a foreign protein Section 2 Cancer Chemotherapy一 Alkylating Agents （烷基化试剂）1 Nitrogen mustards （氮芥）mechlorethamineMechanism of Action氮丙啶鎓Alkylation of guanine in DNA by an alkylating agentOnce alkylation occurs, th
5、e alkylated sites become prone to cleavage 鸟嘌呤2. Melphalan （美法伦）L- L-Phenylalanine mustard or L-PAM L-PAM can be preferentially transported into cells, with the assistance of L-amino acid active transporter3. Cyclophosphamide （环磷酰胺） Reduced nucleophilicity because of the amide-like phosphoramide lin
6、kage Less likely to form an aziridinium ion Chemically more stable Requires metabolic activation (pro-drug)Cyclophosphamide （环磷酰胺）Metabolic activation of cyclophosphamideNon enzymatic丙烯醛？Synthesis of Cyclophosphamide （环磷酰胺的合成）Acidic hydrolysis of cyclophosphamide pH 4.0-6.0 （环磷酰胺的酸性水解）氮芥磷酰二氯3-氨基丙醇Ot
7、her Alkylating Agents - Aziridine Derivatives Less reactive agentsAziridine is a three-membered nitrogen heterocycle that reacts with nucleophiles in order to relieve ring stain 氮丙啶为三元杂环，和亲核试剂或基团反应开环，可释放环的张力三乙蜜胺替哌塞替哌氮丙啶衍生物， 乙撑亚胺类提高抗肿瘤作用 减少毒副作用 白血病前药 P450作用下转化为替哌 乳腺癌最早用于临床安徽阜阳大头娃Thiotepa（塞替哌）and its
8、metabolic product TEPA （替哌）塞替哌pKa=6.0Other Alkylating Agents- Quinone as transporterQuinone part can reduce the electron density, decreased toxicity 醌部分可降低电子云密度，降低药物的毒性Quinone part can interfere enzymatic Re-Ox, inhibit tumor cell division 醌类化合物干扰酶系统氧化-还原过程，抑制肿瘤细胞的有丝分裂癌抑散三亚胺醌卡波醌Metabolic activation
9、of quinone aziridine还原单氢醌氢醌Activation of the aziridine partOther Alkylating Agents-Mitomycin C（丝裂霉素 C）Quinone moiety, the aziridine ring, the carbamate Poor oral absorption, administered IV Treat pancreatic cancer, 胰腺癌antibioticBio-reductive activation of mytomycin C and DNA alkylationStability of M
10、itomycin C（三） Methyl sulfonate （甲磺酸酯类） Busulfan， 白消安，马利兰CH3SO3 is a very good leaving group （甲磺酸基是很好的离去基团）对白血病疗效显著（四）Nitrosoureas （亚硝基脲类）Carmustine，卡莫司汀 Mechanism of Action Reactive speciesReactive speciesReactive speciesReactive speciesFormation of a vinyl cation from carmustineTextbook, page 544,
11、图21-1广谱抗肿瘤活性，可通过BBBSynthesis of Nirosoureas （亚硝基脲类）CarmustineOther Nitrosourea analogs洛莫司汀司莫司汀尼莫司汀（五）三氮烯咪唑类衍生物Dacarbazine （DTIC）达卡巴嗪Proposed metabolism and mechanism of action of dacarbazine5-Amino-4-carboxamide5-（3，3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamideDTIC 主要用于治疗黑色素病、霍杰金氏病鸟嘌呤烷基化鸟嘌呤被DTI
12、C（diazomethane）烷基化六：肼类， Procarbazine （丙卡巴肼）Metabolic activation of procarbazineProdrug偶氮甲基肼二、Cisplatin （顺铂）Mechanism of Action of Cisplatin 与鸟嘌呤碱基N7配位形成五元环，扰乱DNA的正常双螺旋，使局部变性失活 DNA的复制停止Note: only the cis-isomer is active三、Bleomycin, Dactinomycin D, Homoharringtonine博来霉素、放线菌素D和高三尖杉酯碱Bleomycins: antitu
13、mor antibiotic，糖肽类 discovered in 1966 Isolated from Streptomyces verticillus 放线菌The two sugar ring: possible cell recognition and uptake site The imidazole, amide and the amine: Iron 2+ (Fe2+) chelating site The thiazole rings（二噻唑环）: DNA binding sites主要用于治疗皮肤癌二噻唑糖咪唑嘧啶2、 Dactinomycin D,放线菌素DIsolated
14、from Streptomyces parvullusThis ring system is aromatic, planar, can intercalate or insert into DNA between base pair stepsHomoharringtonine, 高三尖杉酯碱Alkaloid, 生物碱 Isolated from homoharringtonine plant， 三尖杉植物 Inhibit protein synthesis; DNA synthesis中国协和医科院，黄量院士，国家科技进步一等奖四、Antitumor reagents Topoisomer
15、ase as targets 作用于DNA拓扑异构酶的药物Topoisomerases catalyze and guide the unknotting of DNA by creating transientbreaks in the DNA using a conserved Tyrosine as the catalytic residueTop I and Top II : different function（一）Camptothecin（喜树碱）, Hydroxy camptothecin （羟基喜树碱）Topisomerase I inhibitors Camptothecin
16、 is a natural product Addition of the hydroxyl and dimethylaminomethyl groups improved watersolubility and reduced the occurrence of unpredictable side effects Mechanism of Action: cause single strand breaks in DNA（二）Anthracyclines （阿霉素类属蒽醌类） Topoisomerase II inhibitors A tetracyclic quinone containing ring nucleus to which is attached a unique daunosamine sugar Reddish in color First isolated from the fermenta
