CELLULAR SELECTIVITY OF ANTIMETABOLITES

其目的是开发更多的选择性治疗肿瘤 疾病的基础上确定的因素是预测 肿瘤细胞对抗代谢物的敏感性和抗性。 初始 研究将集中在确定细胞的决定因素， 对1-β-D-阿拉伯呋喃糖基胞嘧啶（araC）的反应， 代谢调节剂如DL-亚叶酸（dL-CF）在 选择性改变5-氟尿嘧啶（FUra）的治疗效果 和5-氟脱氧尿苷（FdUrd）。 顺铂在增强肿瘤细胞增殖中的作用 氟嘧啶+ dL-CF和阿糖胞苷的治疗效果也将 评估。 对于涉及araC的研究，小鼠白血病L1210移植 腹膜内和皮下注射小鼠结肠癌No.26 皮下移植并且腹膜内移植的淋巴瘤P-388将被 根据它们对araC的不同敏感性使用。 个确定 氟嘧啶将在具有差异的细胞中进行。 敏感性和不同细胞内胸苷酸浓度 合成酶和叶酸辅因子库。 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） 预先存在的池），人结肠癌205号和B-16黑色素瘤 含有相对较低的叶酸池。 araC的特定研究 包括：1）同时定量araCTP池和保留 以及将araC掺入肿瘤和骨髓的DNA中， 肠粘膜; 2）评估cis-DDP对araC的体内作用 反应的决定因素。 这些研究将比较长期持续的 低剂量输注vs高剂量短时间输注。 外贸 氟嘧啶将侧重于确定最佳条件， 叶酸的增强作用 可能存在的关系 在限定的叶酸的血浆浓度、细胞内叶酸 正常和肿瘤中dTMP-合酶的库以及抑制和恢复 将检查细胞。 这些研究应提供基本信息 关于体内药物作用的生物化学和药理学基础 并且所获得的结果应该允许设计改进的临床 方案和癌症患者的反应验证。

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.