Application of new methodology for preclinical development of anticancer drugs : With special focus on camptothecin derivatives and the cyanoguanidine CHS 828

Abstract: This work describes the development and evaluation of new methods for preclinical anticancer drug development. The methods were specifically applied to study camptothecin analogues and the new compound CHS 828 (N-(4-chlorophenoxyhexyl)-N'-cyano-N"-4-pyridylguanidine) currently in early clinical trials.The tumour type-specific patterns of cytotoxicity of several anticancer drugs were evaluated ex vivo in fresh human tumour cells from patients using a non-clonogenic cytotoxicity assay (FMCA). The activity pattern ex vivo correlated well with known clinical activity.The camptothecin analogues topotecan, irinotecan and its active metabolite SN-38 were studied and differential activity patterns were observed in fresh human tumour cells but not in a panel of ten human tumour cell lines. Topotecan showed synergistic interactions with cisplatin in a high fraction of fresh human tumour samples, while CHS 828 seemed to interact positively with melphalan.CHS 828 showed a high activity in vivo on MCF-7 breast cancer and NYH small-cell lung cancer xenografts in nude mice, at doses with low host animal toxicity.A recently described in vivo hollow-fiber model, where tumour cells were cultured in semipermeable fibers, was developed further. The model allowed simultaneous monitoring of antitumour effect, host animal toxicity and pharmacokinetics in immunocompetent rats. In one study, the hollow fibers were filled with cells from breast-cancer cell lines, and the effectand pharmacokinetics of some standard cytotoxic agents and CHS 828 was measured. CHS 828 showed the highest activity of the drugs studied, and the effect was more pronounced when the drug was administered five days instead of one. Tumour cells from patients with chronic lymphocytic leukaemia and ovarian cancer were also cultured in the hollow fibers, and promising antitumour effect of CHS 828 was demonstrated in vivo.The results indicate a feasibility of using primary human tumour cells from patients in anticancer drug development and they also describe a new in vivo hollow-fiber model that can be used to study drug pharmacokinetics, toxicity and antitumour effect. The preclinical data on the cyanoguanidine CHS 828 appears promising.