Turcotte J G, Srivastava S P, Steim J M, Calabresi P, Tibbetts L M, Chu M Y
Biochim Biophys Acta. 1980 Sep 8;619(3):619-31. doi: 10.1016/0005-2760(80)90111-3.
Among events limiting the effectiveness of cancer chemotherapy are the general lack of preferential uptake of anticancer drugs by tumor cells and the occurrence of drug resistance. An approach has been undertaken to explore whether or not such events can be favorably altered or circumvented therapeutically by development of a new class of anticancer molecules, cytotoxic liponucleotide analogs. The design of cytotoxic liponucleotide analogs encompasses both biochemical and biophysical aspects of liponucleotide and glycerophospholipid structure and metabolism. Several cytotoxic liponucleotide analogs of cytidine diphosphate diacylglycerol (CDPdiacylglycerol/dCDPdiacylglycerol), containing the 1-beta-D-arabinofuranosyl moiety, were tested for antitumor activity. Multispecies ara-CDPdiacylglycerol (1-beta-D-arabinofuranosylcytosine 5'-diphosphate diacylglycerol), which contains egg lecithin-derived mixed fatty acyl chains, was more active than 1-beta-D-arabinofuranosylcytosine (ara-C), a clinically used anticancer drug, against leukemia L5178Y and P388 ascites cells in mice. At identical single doses (50 mg/kg per day times 4) administered intraperitoneally, ara-CDPdiacylglycerol prolonged the life spans of L5178Y tumor-bearing mice 93%, while ara-C prolonged life by 18%. Ara-CDPdiacylglycerol increased life spans of P388 tumor-bearing mice by 357% at doses of 50 mg/kg per day times 4; the maximum increase with ara-C was 159% (85 mg/kg per day times 4). Against a P388 ara-C-resistant cell line (P/Ara-C, kinase deficient) in mice, ara-CDPdiacylglycerol prolonged survival times by 34% at a dose of 50 mg/kg per day times 4 and by 55% at 75 mg/kg per day times 4; the drug was not active against two other ara-C-resistant murine leukemia mutants (CA 55, CA5b). With cell line-derived human colon carcinoma HCT-15 grown in mice immunosuppressed with anti-thymocyte serum, ara-CDPdiacylglycerol at a single daily dose of 50 mg/kg per day times 4 significantly reduced tumor weights to 21% of the controls; the same dose schedule of ara-C caused no observable reduction of tumor weights. Results of these preliminary antitumor evaluations indicate that cytotoxic liponucleotide analogs should be investigated further to determine their potential as antineoplastic molecules.
限制癌症化疗效果的因素包括肿瘤细胞普遍缺乏对抗癌药物的优先摄取以及耐药性的出现。人们已经采取一种方法来探索是否可以通过开发一类新型抗癌分子——细胞毒性脂核苷酸类似物，在治疗上有利地改变或规避这些情况。细胞毒性脂核苷酸类似物的设计涵盖了脂核苷酸和甘油磷脂结构与代谢的生物化学和生物物理方面。测试了几种含有1-β-D-阿拉伯呋喃糖基部分的胞苷二磷酸二酰基甘油（CDP二酰基甘油/dCDP二酰基甘油）的细胞毒性脂核苷酸类似物的抗肿瘤活性。含有卵磷脂衍生的混合脂肪酰链的多物种阿糖胞苷二磷酸二酰基甘油（1-β-D-阿拉伯呋喃糖基胞嘧啶5'-二磷酸二酰基甘油），在对抗小鼠白血病L5178Y和P388腹水细胞方面，比临床使用的抗癌药物1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷）更具活性。以相同的单次腹腔注射剂量（每天50 mg/kg，共4次）给药时，阿糖胞苷二磷酸二酰基甘油使L5178Y荷瘤小鼠的寿命延长了93%，而阿糖胞苷使寿命延长了18%。在每天50 mg/kg，共4次的剂量下，阿糖胞苷二磷酸二酰基甘油使P388荷瘤小鼠的寿命延长了357%；阿糖胞苷的最大增幅为159%（每天85 mg/kg，共4次）。在小鼠中，针对一种P/D88阿糖胞苷耐药细胞系（P/Ara-C，激酶缺陷型），阿糖胞苷二磷酸二酰基甘油在每天50 mg/kg，共4次的剂量下使存活时间延长了34%，在每天75 mg/kg，共4次的剂量下延长了55%；该药物对另外两种阿糖胞苷耐药的小鼠白血病突变体（CA 55、CA5b）无活性。对于在接受抗胸腺细胞血清免疫抑制的小鼠中生长的细胞系来源的人结肠癌HCT-15，每天单次剂量50 mg/kg，共4次的阿糖胞苷二磷酸二酰基甘油显著将肿瘤重量降低至对照组的21%；相同剂量方案的阿糖胞苷未观察到肿瘤重量的降低。这些初步抗肿瘤评估的结果表明，应进一步研究细胞毒性脂核苷酸类似物，以确定它们作为抗肿瘤分子的潜力。
