CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo.

A new class of recently discovered antineoplastic agents, the pyridyl cyanoguanidines, exert a potent antitumor activity in rodents after oral administration. Optimization in vitro and in vivo has resulted in the selection of the lead candidate CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine). CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells. In a study using a panel of cell lines with different resistance patterns, the effects of CHS 828 showed a low correlation with the activity patterns of known anticancer agents, and no sensitivity to known mechanisms of multidrug resistance was observed. In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. In conclusion, CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.

The rat Subcutaneous Air Sac model: a quantitative assay of antiangiogenesis in induced vessels.

A new in vivo experimental model--the Subcutaneous Air Sac (SAS) model-has recently been presented to replace a previous in vivo rabbit cornea assay where neovascularisation was induced by chemical injury of the cornea or by implantation of tumour cells intracorneally, a methodology which is believed to cause severe pain to the animals. In the SAS model, an air sac is induced by injection of air subcutaneously on the back of the animal. After 10-14 days the air sac appears as an almost transparent avascular membrane in which induction of new vessels can be studied. We present recent developments of this technique: In the SAS-tumour technique, vascular endothelial growth factor-producing tumour cells are inoculated subcutaneously directly on the membrane, and the formation of new vessels is measured 8 days later. In the SAS-pellet technique, slow-release pellets containing angiogenic factors, basic fibroblast growth factor or vascular endothelial growth factor are implanted on the subcutaneous membrane by a simple operation. The formation of new vessels is measured 10 days later. The ability of the SAS-tumour- and SAS-pellet techniques to detect an antiangiogenic effect of a systemically administered compound was investigated using the fumagillin analogue TNP-470 (o-chloroacetyl-carbamoyl)-fumagillol) as a positive control given subcutaneously for 7 and 9 days, respectively. At a dose of 10 mg TNP-470/kg/day the angiogenesis was reduced by approximately 70% in the SAS-tumour technique and by 40-60% in the SAS-pellet technique. The animals were unaffected by the SAS methodology. The SAS-tumour and SAS-pellet models are considered complementary and make use of simple and almost similar techniques which facilitate the evaluation.