CELLULAR SELECTIVITY OF ANTIMETABOLITIES

目标是开发更多针对肿瘤的选择性治疗方法。 基于对可预测的因素的识别的疾病 肿瘤细胞对抗代谢药物的敏感性和耐药性。首字母 研究将集中在识别细胞决定因素上。 对1-β-D-阿拉伯呋喃胞苷(Arac)的反应和认识 代谢调节剂如dL-亚叶酸(dL-CF)在 选择性改变5-氟尿嘧啶(Fura)的疗效 和5-氟代脱氧尿苷(FdUrd)。顺铂在提高人卵巢癌疗效中的作用 氟嘧啶+dL-CF和Arac的治疗效果也将是 已评估。对于涉及Arac的研究，移植了小鼠白血病L1210 小鼠26号结肠癌腹内和皮下移植瘤的研究 移植的S.C.淋巴组织瘤P-388皮下注射。将会是 使用，基于它们对Arac的差分敏感性。使用以下选项确定 氟嘧啶类药物将在有分化的细胞中进行 胸腺嘧啶核苷的敏感性和细胞内浓度的不同 合成酶和叶酸辅助因子池。这些细胞系包括白血病 L1210、P-1798淋巴肉瘤、大鼠结肠腺癌(均为高表达 人结肠癌205号和B-16黑色素瘤 含有相对较低的叶酸库。与ARAC进行的具体研究 包括：1)同时量化araCTP池和保留率 并将Arac掺入肿瘤和骨髓的DNA中，并 肠粘膜；2)顺铂对ARAC的体内效应 反应的决定因素。这些研究将比较持续时间较长的 低剂量的输液与高剂量的短时间输液。研究对象： 氟代嘧啶将专注于确定最佳条件 叶酸对它们的增强作用。存在一种可能的关系 在确定的叶酸血浆浓度、细胞内叶酸 正常组织和肿瘤组织中DTMP-合成酶的池与抑制和恢复 将对细胞进行检查。这些研究应提供基本信息 关于体内药物作用的生化和药理学基础 所获得的结果应该允许设计改进的临床 治疗方案和癌症患者反应的验证。

The objective is to develop more selective treatments for neoplastic diseases based on the identification of factors which are predictive for the tumor cells' sensitivity and resistance to antimetabolites. Initial studies will focus on the identification of cellular determinants of response to 1-Beta-D-arabinofuranosylcytosine (araC), and on understanding the role metabolic modulators such as dL-leucovorin (dL-CF) play in selectively alterating the therapeutic efficacy of 5-fluorouracil (FUra) and 5-fluorodeoxyuridine (FdUrd). The role of cisplatin in enhanceing the therapeutic efficacy of fluoropyrimidines + dL-CF and araC will also be evaluated. For studies involving araC, mouse leukemia L1210 transplanted intraperitoneally and subcutaneously, mouse colon carcinoma no. 26 transplanted s.c. and the lymphoid tumor P-388 transplanted i.p. will be used, based on their differential sensitivity to araC. Determinations with fluoropyrimidines will be carried out in cells with differential sensitivity and with different intracellular concentrations of thymidylate synthase and folate cofactor pools. These cell lines include leukemia L1210, P-1798 lymphosarcoma, rat colon adenocarcinoma (both with high pre-existing pools), human colon carcinoma no. 205 and B-16 melanoma containing relatively lower folate pools. Specific studies with araC include: 1) the simultaneous quantitation of araCTP pools and retention and incorporation of araC into DNA of tumors and of bone marrow and intestinal mucosa; 2) assessment of the in vivo effects of cis-DDP on araC determinants of response. These studies will compare prolonged continuous infusions of low doses vs short infusions of high doses. Studies with fluoropyrimidine will focus on the identification of optimal conditions for their potentiation by folates. The existence of a possible relationship between a defined plasma concentration of folates, intracellular folate pools and inhibition and recovery of dTMP-synthase in normal and tumor cells will be examined. The studies should provide fundamental information concerning the biochemical and pharmacological basis of drug action in vivo and the results obtained should allow the design of improved clinical protocols and the verification of response in patients with cancer.