title: Anti-tumor efficacy of Cloretazine (VNP40101M) alone and in combination with fludarabine in murine tumor and human xenograft tumor models.
abstract: 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.
authors.affiliation: Vion Pharmaceutical, Inc., 4 Science Park, New Haven, CT 06511, USA. lzheng@vionpharm.com
authors.forename: Li-mou
authors.initials: LM
authors.lastname: Zheng
authors.forename: Zujin
authors.initials: Z
authors.lastname: Li
authors.forename: Lanzhen
authors.initials: L
authors.lastname: Liu
authors.forename: Bai Louis
authors.initials: BL
authors.lastname: Song
authors.forename: Ivan
authors.initials: I
authors.lastname: King
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015431:Weight Loss; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine