Preclinical antitumor activity and pharmacokinetics of methyl-2-benzimidazolecarbamate (FB642).
Methyl-2-benzimidazolecarbamate (carbendazim, FB642) is an anticancer agent that induces apoptosis of cancer cells. In vitro, FB642 demonstrated potent antitumor activity against both the murine B16 melanoma (IC50 = 8.5 microm) and human HT-29 colon carcinoma (IC50 = 9.5 microm) cell lines. FB642 was also highly active against both murine tumor models and human tumor xenografts at varying doses and schedules. In the murine B16 melanoma model, T/C values > 200 were observed. In the human tumor xenograft, FB642 produced tumor growth inhibition of greater than 58% in five of the seven xenograft models evaluated. Partial and complete tumor shrinkage was noted with FB642 against the MCF-7 breast tumor model. Pharmacokinetic studies in rats demonstrated that oral absorption of FB642 was variable and may be saturated at the 2000 mg/kg dose level since higher doses failed to produce a further increase in the area under the time concentration curve. Toxicity of FB642 in vivo appeared to be dose-dependent. Lower doses in the range of 2,000-3,000 mg/kg were better tolerated, while still preserving antitumor activity. Evaluation of FB642 in phase I clinical trials of adult patients with advanced malignancies is currently ongoing.
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio 78245-3217, USA.
Desirée
D
Hao
Jinee D
JD
Rizzo
Stephanie
S
Stringer
Rodney V
RV
Moore
Jennifer
J
Marty
Daniel L
DL
Dexter
Gina L
GL
Mangold
James B
JB
Camden
Daniel D
DD
Von Hoff
Steven D
SD
Weitman
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D013810:Therapeutic Equivalency; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002219:Carbamates; C006698:carbendazim