Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow

Hepsulfam (1,7-heptanediol disulfamate, NSC 329680) is a new antineoplastic alkanesulfonate agent which has demonstrated a broader preclinical activity than busulfan. The compound is currently undergoing clinical trials. We have studied the activity of hepsulfam and busulfan simultaneously in human tumor xenografts in vitro in a clonogenic assay and in vivo in tumor-bearing Animals in order to assess the activity of both compounds in model systems of slowly growing malignancies. In a total of 37 different tumors of various histologies, both agents demonstrated broad spectrum in vitro activity. The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively. At a concentration of 1.0 micrograms/ml, hepsulfam was active in eight of 37 tumors (22%) in the clonogenic assay, whereas busulfan effected inhibition of colony formation in one of 37 lines (3%). At the same concentration, however, hepsulfam demonstrated a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors, whereas busulfan did not reveal a myelosuppressive effect. Evaluation of equitoxic concentrations in vitro revealed a higher activity of hepsulfam, especially in non-small cell lung Cancer. In tumor-bearing nude mice, the approximate LD10 dose was determined as 150 mg/kg single bolus injection given i.p. on day 1 for both compounds. Hepsulfam demonstrated superior in vivo activity in a large cell lung Cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)