Wingen F, Sterz H, Blum H, Möller H, Pittermann W, Pool B L, Sinn H J, Spring H, Schmähl D
J Cancer Res Clin Oncol. 1986;111(3):209-19. doi: 10.1007/BF00389236.
The aim of this study was to investigate whether the newly synthesized bisphosphonic acid-linked N-Lost derivative BAD retains bone-seeking and cytostatic properties. The paper describes experiments on mutagenicity in vitro and on toxicity in vivo. BAD is characterized by very low mutagenic activity toward histidine auxotrophic Salmonella typhimurium strains. Cytotoxic effects were tested in rat osteosarcoma and in Walker carcinosarcoma 256B. The LD50 of i.v. injected BAD was 146 mg/kg. Acute toxicity is probably caused by calcium complexing of the bisphosphonate part of the molecule. Labeling experiments showed moderate accumulation in bone and osteosarcoma, as well as in lung metastases. BAD effected high tumor growth inhibition in osteosarcoma and Walker carcinosarcoma-bearing rats and marked prolongation of survival; histologic and radiographic examination revealed rapid calcification of osteosarcoma and lung metastases. BAD-pretreatment produced protective effects against osteolysis induced by intratibially implanted Walker carcinosarcoma ascites cells. The cytostatic efficacy of equitoxic doses of BAD in rat osteosarcoma is comparable to that of dacarbazine and in Walker carcinosarcoma to that of melphalan.
本研究的目的是调查新合成的双膦酸连接的N-Lost衍生物BAD是否保留亲骨特性和细胞抑制特性。本文描述了体外致突变性和体内毒性实验。BAD的特点是对组氨酸营养缺陷型鼠伤寒沙门氏菌菌株的致突变活性非常低。在大鼠骨肉瘤和沃克癌肉瘤256B中测试了细胞毒性作用。静脉注射BAD的半数致死量为146mg/kg。急性毒性可能是由分子中双膦酸盐部分的钙络合引起的。标记实验表明，BAD在骨骼、骨肉瘤以及肺转移灶中有中度蓄积。BAD对荷骨肉瘤和沃克癌肉瘤大鼠的肿瘤生长有高度抑制作用，并显著延长生存期；组织学和影像学检查显示骨肉瘤和肺转移灶迅速钙化。BAD预处理对胫骨内植入沃克癌肉瘤腹水细胞诱导的骨溶解产生保护作用。在大鼠骨肉瘤中，等毒性剂量的BAD的细胞抑制效力与达卡巴嗪相当，在沃克癌肉瘤中与美法仑相当。
