Activity of boanmycin against colorectal cancer

Abstract

Boanmycin (Bleomycin A6, BAM), a new antitumor antibiotic, was isolated from many components of bleomycin (BLM) produced by streptomyces pingyangensis which were obtained from a soil sample collected in Pingyang County, Zhejiang Province, China. Boanmycin has a similar chemical structure to that of BLM, but the terminal amine moiety is different[1]. Pingyangmycin (bleomycin A5), one of multicomponent bleomycin complex produced by the strain, was found to have a high activity against a wide spectrum of murine transplantable tumors, but have a relatively low pulmonary toxicity in mice[2-4]. Pingyangmycin, as a single agent, shows marked inhibition on the growth of human colon cancer, stomach cancer and nasopharyngeal cancer xenografts in nude mice[5-7]. It has been widely used clinically in the treatment of tumors since 1979 in China[8]. Because of a good antitumor efficacy of pingyangmycin as a single agent and low marrow toxicity, attempts have been made to develop new superior bleomycin derivatives[9]. BAM, a minor component of bleomycin complex, was also found to be highly active against murine tumors, human liver cancer and colorectal xenografts in nude mice, and markedly inhibit the spontaneous pulmonary metastasis of Lewis carcinoma in mice[10-14]. BAM-monoclonal antibody immunoconjugates were highly effective against related human tumor in vivo and in vitro[15-19]. BAM also reached a higher concentration and remained for a longer time in murine transplantable carcinomas as compared with other bleomycin components[3]. As observed under electron microscopy, the pulmonary toxic damage caused by BAM was less than that induced by bleomycin[20]. Phase I clinical study of BAM showed no myelosuppression and cardiac toxicity, and its major adverse reactions were fever, gastrointestinal reactions and hardening at the site of i.m. injection. All adverse effects disappeared after discontinuation of the therapy[21]. An ideal animal model for cancer is one that mimics human disease in every respect. Most tumor xenograft studies, including colorectal tumor, for the evaluation of antitumor activity of drugs used subcutaneous implantation system due to its convenience and access to direct detection and therapeutic effect. However, those models have limitations for the study of interaction of tumor cells with their relevant organ environment or or gan distribution of drugs. Alteration of microenvironment surrounding tumor tissue will not only influence growth and spread of tumor but also is important for drug delivery[22-24]. Recently, use of orthotopic models for the growth of tumors in mice or rat has aroused more interest, including lung cancer, colorectal cancer, breast cancer, pancreatic cancer, etc[25-30]. However, whether such orthotopic colorectal tumor models apply to the evaluation of new anticancer agents remains unknown. In the present study, human colorectal tumor xenograft model in nude mice and the orthotopic model of murine colon cancer were used to clarify the antitumor effect of BAM in comparison with that of mitomycin C and 5-fluorouracil, drugs commonly used in clinics against colorectal cancer. We attempted to determine the effect of BAM against colorectal cancer and whether the organ microenvironment could influence the response of a murine colon cancer to systemic therapy with BAM.