Cytotoxic effect in vivo and in vitro of CHS 828 on human myeloma cell lines.

CHS 828 is a pyridyl cyanoguanidine with promising antitumor activity both in vitro and in vivo, and has previously been found especially active against tumor cells obtained from patients with B cell chronic lymphocytic leukemia. In the present study the cytotoxic effect in vitro of CHS 828 was investigated on a panel of 10 human myeloma cell lines using the fluorometric microculture cytotoxicity assay. CHS 828 induced a concentration-dependent, but variable decrease in tumor cell survival in the cell line panel with inhibitory concentrations 50% (IC50) in the range 0.01-0.3 microM. These concentrations are below those achievable in vivo. There was no detectable dependence on P-glycoprotein-mediated or GSH-associated drug resistance and the drug showed low to moderate cross-resistance with standard drugs, including melphalan, vincristine and doxorubicin. Furthermore, sensitivity to CHS 828 showed no apparent relationship to growth factor dependence, tumor progression or phenotypic variability. CHS 828 was also tested in vivo using a hollow fiber model in rats with three of the cell lines. The results indicate a high cytotoxic activity of CHS 828. Overall, the results show a high cytotoxic activity of CHS 828 in the myeloma models, which might warrant its further development against myeloma.

A Phase I study of CHS 828 in patients with solid tumor malignancy.

CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1-5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 +/- 1.3 h and half-life was 2.1 +/- 0.52 h (mean +/- SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.