LOW DOSE SURAMIN AS A CHEMOSENSITIZER OF BLADDER CANCER TO MITOMYCIN C

Abstract

We have reported that acidic and basic fibroblast growth factors expressed in solid tumors induce broad-spectrum chemoresistance and their nonspecific inhibitor suramin (Sigma Chemical Co., St. Louis, Missouri) at nontoxic concentrations enhances the activity of chemotherapeutic agents. In the current study we evaluated whether low dose suramin enhances tumor sensitivity to mitomycin C (MMC) (Bristol-Myer Squibb Co., Wallingford, Connecticut). Three-dimensional histocultures of RT4 (American Type Culture Collection, Rockville, Maryland) xenograft tumors and tumors from patients with bladder cancer were treated with MMC with or without 20 microM suramin. For in vivo studies mice bearing RT4 tumors received physiological saline, MMC (3 mg/kg), suramin (10 mg/kg) or MMC/suramin combination every 3 or 4 days. Two MMC schedules were studied, namely subtherapeutic (3 treatments) and therapeutic (6 treatments) schedules. Suramin enhanced MMC activity in xenograft and patient tumor histocultures by greater than 2-fold. The chemosensitization effect was observed in all patient tumors (2 superficial and 9 muscle invading lesions). In animals tumors in the control and suramin groups increased to approximately 3 to 5 times the initial size. The subtherapeutic MMC schedule retarded tumor growth but did not produce tumor shrinkage, whereas the therapeutic MMC schedule reduced tumor size by 27%. The addition of suramin enhanced MMC activity. Respective tumor sizes were 40% and 63% of the sizes after subtherapeutic and therapeutic MMC alone (p <0.01). The combination groups showed body weight losses similar to those of MMC alone. Low dose suramin enhanced the in vitro and in vivo activity of subtherapeutic and therapeutic MMC without enhancing host toxicity, thus, providing proof of concept for evaluating low dose suramin as a chemosensitizer with MMC in bladder cancer.