Exploring the mechanisms of action of FB642 at the cellular level.
FB642(methyl-2-benzimidazolecarbamate, carbendazim) is a systemic fungicide belonging to the benzimidazole family with antitumor activity against a broad spectrum of tumors both in vitro and in vivo such as pancreas, prostate, colon, and breast. Although the preclinical antitumor activity of FB642 has been well explored, its mechanism of action has not been as well delineated. Previous studies indicate that FB642 may interfere with mitosis and thus may disrupt or inhibit microtubule function resulting in apoptosis. This study seeks to determine if FB642 is a sufficiently novel agent worthy of further development by examining the effect of FB642 on apoptosis, the cell cycle, p53-positive and -negative tumors, and drug-resistant and MDR cell lines. The results of this present study indicate that FB642 increases the degree of apoptosis in all examined tumor cell lines, may induce G2/M uncoupling, may selectively kill p53 abnormal cells, and exhibits antitumor activity in drug- and multidrug-resistant cell lines. The induction of apoptosis by FB642, particularly in p53-deficient cells, its impressive in vivo activity against a broad spectrum of murine and human tumors, as well as an acceptable toxicity profile in animals, make FB642 an excellent candidate for further evaluation in clinical trials in cancer patients.
Hammond
L A
LA
Institute for Drug Development, Cancer Therapy & Research Center, 8122 Datapoint Drive 650, San Antonio, TX 78229, USA. lhammond@saci.org
Davidson
K
K
Lawrence
R
R
Camden
J B
JB
Von Hoff
D D
DD
Weitman
S
S
Izbicka
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000473:pathology; D002219:Carbamates; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016158:Genes, p53; D006801:Humans; D007938:Leukemia / Q000473:pathology; D007942:Leukemia, Experimental / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002219:Carbamates; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; C006698:carbendazim