PHOTODYNAMIC THERAPY‐INDUCED HYPOXIA IN RAT TUMORS and NORMAL TISSUES

AbstractThe administration of misonidazole (MISO) to Fischer x Copenhagen rats whose R3327‐H prostate tumors were treated with photodynamic therapy (PDT) produced enhanced tumor growth delays and cures. This potentiation of PDT by MISO was previously observed with R3327‐AT tumors and was postulated to result from drug cytotoxicity of naturally‐occurring and PDT‐induced hypoxic cells. Radioactively‐labelled MISO has been developed as a marker for tissue p02at the cellular level and [3H]MISO was administered to R3327‐AT and R3327‐H tumor‐bearing rats before and after standard PDT treatments. The amount of3H in tissues 24 h after drug administration was a measure of‘bound MISO’which reflects average tissue oxygenation. [3H]MISO retained in R3327‐AT tumors was ˜4x and in liver tissue ˜2x that retained in muscle, heart, brain and R3327‐H tumors (1x). Tumors treated with Photofrin II and lased with 1000 J showed a 6‐fold increase in retained [3H]MISO in R3327‐H tumors and a 2‐fold increase in retained [3H]MISO in R3327‐AT tumors. The absolute levels of retained3H in both tumors after PDT were similar. These data provide direct evidence that PDT induces rapid hypoxia in both tumors. When the gastrocnemius muscle of the rat leg was similarly treated, the amount of [3H]MISO retained was ˜4x greater than that in untreated muscle. This result suggests that PDT‐induced hypoxia is not selective to just tumor tissue. These data suggest that the hypoxia‐inducing property of PDT might be exploited in combination with hypoxic cell cytotoxins to produce improved tumor responses and cures.