In vivo antitumor effects of bis-benzimidazole derivatives in mouse melanoma and lung cancer models

BACKGROUND: The development of new antitumor agents on the basis of benzimidazoles opens new opportunities for treatment of the malignant tumors, including those refractory to conventional therapies. The benzimidazole derivatives demonstrate wide spectrum of biological activities, specifically antineoplastic effects, and high-level cytotoxicity toward human’s tumor cell lines. The exploration of antineoplastic effects of new synthetic benzimidazole derivatives in in vivo models of tumor growth will help the development of the effective doses and cancer treatment regimens with the use of such compounds.

AIM: To assess the antineoplastic effects of the benzimidazole derivatives — monomeric compound MB₂Py(Ac) and dimeric compound DB₂Py(3) — in the continuous cellular models of Lewis lung carcinoma (LLC) and melanoma B16 in mice.

MATERIALS AND METHODS: In vivo assessment of antineoplastic effects was performed in the continuous mouse models of Lewis lung carcinoma (LLC) and B16 melanoma after a single intravenous injection of MB₂Py(Ac) and DB₂Py(3). Irinotecan was used as a comparator drug. Antitumor effects were measured via standard parameters, such as tumor growth inhibition (TGI%) and tumor growth rate (TGR).

RESULTS: The study compounds DB₂Py(3) and MB₂Py(Ac) used in the study doses and regimen demonstrated mild antitumor effect in the model of murine solid tumors (TGI <50%). In melanoma B16 model, the maximum tumor growth inhibition was 15% and 38.5%, respectively, for MB₂Py(Ac) and DB₂Py(3). In the lung carcinoma model, the mild effect was observed, e.g. 8% for MB₂Py(Ac) and 23.4% for DB₂Py(3). The effect of the comparator drug, irinotecan, was more expressive, although short-term. In particular, TGI achieved 52.5% for melanoma B16 and 34.5% for Lewis lung carcinoma (LLC). In general, melanoma B16 was more sensitive to the effects of both bis-benzimidazoles and irinotecan, compared to the lung carcinoma LLC.

CONCLUSION: This study shows that the dimeric compound DB₂Py(3) was the most promising among three study substances in the models of melanoma and lung carcinoma in mice. Nevertheless, its high toxicity imposes the necessity of further optimization for the clinical use. The substance MB₂Py(Ac) demonstrated lowest efficacy, although it may be also explored in the modified treatment regimens.