laromustine and fludarabine

Cloretazine (VNP40101M), a new sulfonylhydrazine alkylating agent, has demonstrated broad-spectrum anti-tumor activity in preclinical studies. In this study, Cloretazine was evaluated both as a monotherapy and in combination with fludarabine in murine tumor and human tumor xenograft models. Cloretazine significantly inhibited the growth of subcutaneously implanted tumors, including B16F10 murine melanoma in C57BL/6 mice, and H460 human lung carcinoma and WiDr human colon carcinoma in athymic nude CD1 mice. The inhibition of tumor growth by Cloretazine was dose dependent, increasing from 42.2 to 87% as the dose escalated from 100 to 150 mg/kg. Cloretazine showed equivalent efficacy but lower toxicity compared to cyclophosphamide in these models. The combination therapy, consisting of a single dose of 10 mg/kg Cloretazine plus five doses of 70 mg/kg fludarabine, given every other day intraperitoneally, significantly increased the long-term survival of BDF1 mice bearing the L1210 murine leukemia. On Day 65 post-tumor implantation, the combination therapy yielded a 90% survival rate compared to 40% for Cloretazine alone and 0% for fludarabine alone.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hydrazines; Injections, Intraperitoneal; Leukemia L1210; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; Sulfonamides; Survival Analysis; Time Factors; Tumor Burden; Vidarabine; Weight Loss; Xenograft Model Antitumor Assays