Influence of the vascular damaging agents DMXAA and ZD6126 on hypericin distribution and accumulation in RIF-1 tumors

Abstract

We investigated the influence of two types of vascular damaging agents (VDAs) (DMXAA vs. ZD6126) and sequence of administration (VDA 24 h before HYP vs. HYP 1 h before VDA) to evaluate the effect on hypericin (HYP) accumulation and distribution in necrotic tumors. Frozen sections of dorsally inoculated RIF-1 tumors were analyzed by fluorescence microscopy and H&E stained for histological evaluation. The localization of HYP was assessed both qualitatively and semi-quantitatively in necrotic tumor, viable tumor, or nontarget host tissue. Whereas the type of VDA did not influence HYP accumulation and distribution, a clear advantage could be seen when administering VDA 24 h before HYP compared to HYP 1 h before VDA, pointing toward the absence of a "trapping" mechanism. In DMXAA-treated and not in ZD6126-treated tumors, spotty fluorescence was observed which is likely to be a consequence of neutrophil phagocytosis. Dexamethasone treatment neither did influence this phenomenon nor did change HYP uptake in necrotic tumor. We conclude that HYP accumulation is optimal when it is administered after VDA injection. We also found that HYP accumulation in necrosis is not changed when using VDAs with different working mechanisms. This insight provides a rationale for tumor necrosis therapy (TNT) using iodine-131-labeled hypericin ([(131)I]-HYP) in combination with VDAs.