Li C J, Miyamoto Y, Kojima Y, Maeda H
Department of Microbiology, Kumamoto University School of Medicine, Japan.
Br J Cancer. 1993 May;67(5):975-80. doi: 10.1038/bjc.1993.179.
Effects of angiotensin II (AT-II)-induced hypertension on the distribution of macromolecules to Walker carcinoma and to bone marrow of SMANCS [poly(styrene-co-maleic-acid)-neocarzinostatin conjugate] were investigated in rats. AT-II-induced hypertension from about 100 to 150 mmHg significantly increased the accumulation of the macromolecular drug SMANCS and 51Cr-labelled bovine serum albumin ([51Cr]BSA), representatives of macromolecular drugs, in tumour tissue. At 1 h after i.v. administration, intratumour concentrations of [51Cr]BSA and SMANCS were elevated by 1.2-1.8-fold. The higher drug accumulation in the tumour that was produced by the artificial hypertension was retained even 6 h after administration. This observation indicates an additive effect to that under normotensive conditions where intratumour macromolecular drug concentrations increase steadily during this period. Furthermore, distributions of these drugs in the bone marrow and the small intestine decreased during artificial hypertension to 60-80% of those in the normotensive state. Therefore, the drug concentration ratios of tumour/bone marrow and tumour/small intestine were increased by 1.8-2.4-fold. A decreased distribution of SMANCS to normal tissues under hypertensive conditions was also confirmed by the significant reduction of its toxicity e.g. leukopenia, diarrhoea, and body weight loss, even at a lethal dose. On the contrary, [3H]methylglucose showed no remarkable difference in tumour or bone marrow accumulation under this hypertensive condition. These results show the advantages of macromolecules over small molecules for AT-II-induced hypertension chemotherapy.
研究了血管紧张素II（AT-II）诱导的高血压对大分子物质在大鼠体内向Walker癌和骨髓的分布以及对SMANCS[聚（苯乙烯-共-马来酸）-新制癌菌素缀合物]分布的影响。AT-II诱导的高血压使血压从约100 mmHg升至150 mmHg，显著增加了大分子药物SMANCS和大分子药物代表物51Cr标记的牛血清白蛋白（[51Cr]BSA）在肿瘤组织中的蓄积。静脉注射后1小时，肿瘤内[51Cr]BSA和SMANCS的浓度升高了1.2至1.8倍。人工高血压导致的肿瘤内较高药物蓄积在给药后6小时仍持续存在。这一观察结果表明，与正常血压条件下在此期间肿瘤内大分子药物浓度稳步增加的情况相比，具有累加效应。此外，在人工高血压期间，这些药物在骨髓和小肠中的分布降至正常血压状态下的60%至80%。因此，肿瘤/骨髓和肿瘤/小肠的药物浓度比增加了1.8至2.4倍。即使在致死剂量下，SMANCS在高血压条件下对正常组织的分布减少也通过其毒性（如白细胞减少、腹泻和体重减轻）的显著降低得到证实。相反，[3H]甲基葡萄糖在这种高血压条件下在肿瘤或骨髓中的蓄积没有显著差异。这些结果显示了大分子相对于小分子在AT-II诱导的高血压化疗中的优势。
