Anticancer Efficacy of HPPH-PDT Synergies with BCG-Immunotherapy or COX-2 Inhibitor in Treating Bladder Cancer

Among the photosensitizers (PSs) developed in our laboratory, 3-(1'-hexyloxy) ethyl-3-devinyl pyropheophorbide-a (HPPH) is undergoing Phase-II multicenter clinical trials for the treatment of head and neck and esophageal cancers. The PS exhibits absorption at 665 nm (in vivo) and shows desired pharmacokinetics with limited skin phototoxicity in patients, compared to FDA-approved Photofrin. This study determined the effect of HPPH-PDT in vitro and in vivo on human bladder cancer (BCa) tissue grown in immune-deficient mice. We observed high tumor uptake/retention of HPPH at 24 h post injection. The anticancer activity of HPPH-PDT was associated with undesirable induction of COX-2, the key enzyme enhancing the production of prostaglandin E2 (PGE2), a pathway we previously found accompanying tumors associated with immune suppression and tumor progression. Combination of COX-2 inhibition with PDT or with BCG-immunotherapy showed an improved rate of tumor cures. Hence, HPPH-PDT in combination with COX-2 inhibitors not only reduces the expression of COX-2, IL-6, VEGF, and PGE2 but also enhances long-term tumor cure.