肿瘤药理学ppt课件.pptVIP

The multidrug resistance gene MDR1, which encodes the cell-surface molecule P-glycoprotein (PGP), can confer resistance to a wide variety of drugs. PGP transports drugs out of the cell, which is a process that requires the presence of two ATP-binding domains. These domains are a defining characteristic of this family of ATP-binding cassette (ABC) transporters. The exact mechanism of drug efflux is not well understood, but might involve either direct transport out of the cytoplasm or redistribution of the drug as it transverses the plasma membrane. Some cytotoxic drugs that are known substrates for PGP include etoposide, daunomycin, taxol, vinblastine and doxorubicin. PGP is modified by sugar moieties (black) on the external surface of the protein. * * 本品为尿嘧啶衍生物。尿嘧啶掺入肿瘤组织的速度较其他嘧啶快。以卤原子代替氢原子合成的卤代嘧啶衍生物中，5-FU抗肿瘤作用最好。由氟原子取代尿嘧啶中的氢原子，由于氟的原子半径和氢的原子半径相近，氟化物的体积与原化合物几乎相等，加之C-F键特别稳定，在代谢过程中不易分解，能在分在水平代替正常代谢物，因而是胸腺嘧啶合成酶（TS）抑制剂。 ????? 氟尿嘧啶的疗效虽好，但毒性也较大，可引起严重的消化道反应和骨髓抑制等副作用。为了降低毒性，提高疗效，研制了大量的衍生物。根据氟尿嘧啶的结构特点，其分子中的N2是主要的修饰部位。替加氟、双氟氟尿嘧啶、卡莫氟、氟铁龙等均为前药，在体内转化为氟尿嘧啶发挥作用，所以毒性较氟尿嘧啶低。 抗肿瘤作用主要由于其代谢活化物氟尿嘧啶脱氧核苷酸干扰了脱氧尿嘧啶苷酸向脱氧胸腺嘧啶核苷酸转变，因而影响了DNA的合成，经过四十年的临床应用，成为临床上常用的抗肿瘤药物，成为治疗肺癌、乳腺癌、消化道癌症的基本药物。 * -Fluorouracil (5-FU; see structure) is converted to three main active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). The main mechanism of 5-FU activation is conversion to fluorouridine monophosphate (FUMP), either directly by orotate phosphoribosyltransferase (OPRT) with phosphoribosyl pyrophosphate (PRPP) as the cofactor, or indirectly via fluorouridine (FUR) through the sequential action of uridine phosphorylase (UP) and uridine kinase (UK). FUMP is then phosphorylated to fluorouridine diphosphate (FUDP), which can be either further phosphorylated to the active metabolite fluorouridine triphosphate (FUTP), or converted to fluorodeoxyuridine diphosphate (FdUDP) by ribonucleotide reductase (RR). In turn, FdUDP c