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ORIGINAL RESEARCH ARTICLE

Effect of Intratumoral Injection of Carboplatin Combined with Pluronic P85 or L61 on Experimental Colorectal Carcinoma in Rats

Tianyi M. Krupka^*, Brent D. Weinberg, Hanping Wu^*, Nicholas P. Ziats^,, and Agata A. Exner^*,1

^* Departments of Radiology, Biomedical Engineering, Pathology, and Anatomy, Case Western Reserve University, Cleveland, Ohio 44106

To whom requests for reprints should be addressed at ¹ Department of Radiology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5056. E-mail: agata.exner{at}case.edu

Pluronic, a poly(ethylene oxide)-poly(propylene oxide)-poly (ethylene oxide) block copolymer, has been shown to enhance the cytotoxic activity of anticancer drugs in various cell lines. In the current study the effect of Pluronic P85 (P85) and Pluronic L61 (L61) on the intratumoral chemotherapy of an experimental adenocarcinoma in rats was examined. A total of 120 subcutaneous tumors (4 per rat) were inoculated in 30 BDIX rats and were treated weekly for 4 weeks with intratumoral injection of carboplatin (CPt) alone or with either P85 or L61. Tumors were monitored weekly and were excised at the endpoint for histologic evaluation. The effect of Pluronic on levels of intracellular ATP was explored as a possible mechanism of sensitization. Results showed that tumors treated with low-dose CPt (2.8 mg/kg) and P85 or L61 exhibited significant reductions in tumor volume after 28 days relative to Day 0 (112.7% ± 34.4%, n = 15; 131.3% ± 55.6%, n = 8) compared with tumors treated with free drug (339.4% ± 75.0%, n = 16). Control tumors treated with either P85 or L61 alone or with saline showed volume increases of 1079.4% ± 143.6% (n = 16), 729.4% ± 202.2% (n = 7), and 1119.2% ± 6.1% (n = 16), respectively. Treatment with high-dose CPt (20.7 mg/kg) led to a 79.3% ± 4.2% reduction in tumor volume, and no differences were noted with addition of P85 or L61. In vitro ATP measurements showed that 28.0 mg/kg of P85 significantly reduced levels of intracellular ATP to 44.7% ± 1.5% of controls, whereas L61 at this concentration depleted ATP levels completely. Results confirm that Pluronic P85 and L61 act as potent sensitizers to carboplatin chemotherapy of the experimental colorectal carcinoma, leading to a significant reduction of tumor growth compared to carboplatin alone. ATP depletion is a possible mechanism for these observed differences.

Key Words: Pluronic • carboplatin • intratumoral injection • chemosensitizer • DHD/K12/TRb rat colorectal carcinoma • ATP