In vivo efficacy and toxicity of intratumorally delivered mitomycin C and its combination with doxorubicin using microsphere formulations

Abstract

The efficacy and toxicity of intratumorally (i.t.) administered anticancer drugs mitomycin C (MMC) and doxorubicin (Dox) incorporated in polymeric microspheres were investigated. Biodegradable sulfopropyl dextran microspheres and their oxidized products were used to load Dox and MMC, respectively. EMT6 mouse mammary cancer cells were injected into the hind leg of BALB/c mice. MMC microspheres, alone or combined with Dox microspheres, were injected i.t. once tumors had reached around 0.3 g. The tumor-plus-leg diameter was measured daily and the delay in time for the tumor to grow to 1.13 g relative to control (TGD) was employed as an indication of therapeutic effect. General toxicity was determined by monitoring weight, appearance and behavior of the mice. Morphology and histology of tumor and heart tissues were also examined. An average 79% TGD was observed after i.t. injection of MMC microspheres. The i.t. co-administration of MMC and Dox microspheres resulted in a 185% TGD. The i.t. injections of the microsphere formulations did not result in visible signs of toxicity in animals. In contrast, systemic (i.e. i.p.) injections of MMC solutions caused considerable general toxicity. This study suggests that i.t. delivery of anticancer drugs by polymeric microspheres is an effective way of improving the therapeutic index for cancer chemotherapy of selected solid tumors under special conditions.