Pal Shipra, Sadhu Arpita Sengupta, Patra Swarup, Mukherjea Kalyan K
Department of Chemistry, Jadavpur University, Kolkata - 700032, India.
J Exp Clin Cancer Res. 2008 Nov 12;27(1):68. doi: 10.1186/1756-9966-27-68.
Cisplatin, a platinum based anticancer drug has played a vital role in the treatment of cancers by chemical agents, but in view of the serious toxicity including nephrotoxicity of cisplatin, various other platinum based drugs have been synthesized and screened to overcome its toxicity. A Pt-ATP compound was prepared in our laboratory hoping to have reduced or no toxicity along with the potentiality of reducing neoplasm growth.
A Pt-ATP compound was prepared. It was first screened for its antineoplastic efficacy. Confirming that, subsequent experiments were carried on to test its toxicity on animals, viz. Albino Swiss mice. The animals were randomly divided into four sets--Set I: Erhlich Ascites Carcinoma (EAC) challenged mice; Set II: Normal mice; Set III: Drug treated mice, Set IVA Cisplatin (CDDP) treated mice, Set IV B EAC challenged Cisplatin treated mice. Set I was used to test antineoplasticity of the drug, Set II and Set III for studying drug toxicity and Set IV was treated with CDDP. Set II was used as a control. Animals were sacrificed after 5 days, 10 days 15 days and 20 days of drug administration on the 6th, 11th, 16th and 21st days respectively for Set I, II and III. Set IVA was sacrificed only on the 16th day and Set IV B on 6th and 11th days. For Set I only tumor cell count and packed cell volume (PCV) of tumor cells were recorded. For Set II and III, aspartate aminotransferase (AST), alanine aminotransferase (ALT) assays were done using serum while blood creatinine and creatine were assayed from blood filtrate. For cytotoxicity assessment liver, spleen and kidney tissues were collected and subjected to scanning electron microscopy (SEM) after extensive treatment. Set IV A was only studied for the biochemical parameters viz. aspartate aminotransferase (AST), alanine aminotransferase (ALT) assays were done using serum while blood creatinine and creatine were assayed from blood filtrate. Set IV B was studied for tumor cell count after treatment with CDDP for 10 days.
Our comparative studies with normal and drug treated animals reveal that the drug does not affect the body weight of the drug treated animals significantly. The biochemical parameters like ALT and AST levels are also within normal limits which rules out hepatotoxicity. The detailed histological studies by SEM reveal that the hepatic, kidney and spleen tissues are not adversely affected by the drug. Comparison of biochemical parameters with the CDDP treated animals show that Pt-ATP is not at all toxic like the CDDP. The Kaplan-Meier analysis of the survival data of Set I has shown promising results with a significance of p < 0.0001.
Set I results are promising and indicating antineoplastic efficacy of the synthesized drug with increased life span of the animals. Biochemical analysis, hematological and SEM studies revealed that the drug was neither nephrotoxic nor hepato-spleeno-toxic under the experimental set up.
顺铂是一种铂类抗癌药物，在化学药物治疗癌症中发挥了重要作用，但鉴于顺铂具有严重的毒性，包括肾毒性，人们已合成并筛选了各种其他铂类药物以克服其毒性。我们实验室制备了一种铂 - 三磷酸腺苷（Pt - ATP）化合物，希望其毒性降低或无毒性，同时具有抑制肿瘤生长的潜力。
制备了一种Pt - ATP化合物。首先对其抗肿瘤疗效进行筛选。确认有疗效后，随后进行实验以测试其对动物（即白化瑞士小鼠）的毒性。将动物随机分为四组——第一组：接种艾氏腹水癌（EAC）的小鼠；第二组：正常小鼠；第三组：药物处理小鼠；第四组A：顺铂（CDDP）处理小鼠，第四组B：接种EAC的顺铂处理小鼠。第一组用于测试药物的抗肿瘤性，第二组和第三组用于研究药物毒性，第四组用CDDP处理。第二组用作对照。分别在给药后的第6天、11天、16天和21天，于第5天、10天、15天和20天后处死第一组、第二组和第三组的动物。第四组A仅在第16天处死，第四组B在第6天和第11天处死。对于第一组，仅记录肿瘤细胞计数和肿瘤细胞的血细胞比容（PCV）。对于第二组和第三组，使用血清进行天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）测定，同时从血液滤液中测定血肌酐和肌酸。为了评估细胞毒性，收集肝脏、脾脏和肾脏组织，并在经过广泛处理后进行扫描电子显微镜（SEM）检查。第四组A仅研究生化参数，即使用血清进行天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）测定，同时从血液滤液中测定血肌酐和肌酸。第四组B在接受CDDP治疗10天后研究肿瘤细胞计数。
我们对正常和药物处理动物的比较研究表明，该药物对药物处理动物的体重没有显著影响。ALT和AST水平等生化参数也在正常范围内，排除了肝毒性。通过SEM进行的详细组织学研究表明，肝脏、肾脏和脾脏组织未受到该药物的不利影响。与CDDP处理动物的生化参数比较表明，Pt - ATP完全不像CDDP那样有毒。第一组生存数据的Kaplan - Meier分析显示出有希望的结果，p值<0.0001，具有显著性。
第一组结果很有希望，表明合成药物具有抗肿瘤疗效，可延长动物寿命。生化分析、血液学和SEM研究表明，在实验条件下该药物既无肾毒性也无肝脾毒性。
