Improvement of Tumor Response by Manipulation of Tumor Oxygenation During Photodynamic Therapy¶

Abstract

Photodynamic therapy (PDT) requires molecular oxygen during light irradiation to generate reactive oxygen species. Tumor hypoxia, either preexisting or induced by PDT, can severely hamper the effectiveness of PDT. Lowering the light irradiation dose rate or fractionating a light dose may improve cell kill of PDT‐induced hypoxic cells but will have no effect on preexisting hypoxic cells. In this study hyperoxygenation technique was used during PDT to overcome hypoxia. C3H mice with transplanted mammary carcinoma tumors were injected with 12.5 mg/kg Photofrin® and irradiated with 630 nm laser light 24 h later. Tumor oxygenation was manipulated by subjecting the animals to 3 atp (atmospheric pressure) hyperbaric oxygen or normobaric oxygen during PDT light irradiation. The results show a significant improvement in tumor response when PDT was delivered during hyperoxygenation. With hyperoxygenation up to 80% of treated tumors showed no regrowth after 60 days. In comparison, when animals breathed room air, only 20% of treated tumors did not regrow. To explore the effect of hyperoxygenation on tumor oxygenation, tumor partial oxygen pressure was measured with microelectrodes positioned in preexisting hypoxic regions before and during the PDT. The results show that hyperoxygenation may oxygenate preexisting hypoxic cells and compensate for oxygen depletion induced by PDT light irradiation. In conclusion, hyperoxygenation may provide effective ways to improve PDT efficiency by oxygenating both preexisting and treatment‐induced cell hypoxia.

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

“…In vivo studies have demonstrated an improved efficacy of photodynamic therapies by temporarily increasing O 2 availability [8,19], but in vitro studies have failed to replicate this [7]. Here, we have recapitulated the treatment-enhancing effects of temporary hyperoxia observed in vivo [8,19] by exposing cells to a short period of hyperoxia during treatment, following chronic culture under physioxia ( Figs.…”

“…Here, we have recapitulated the treatment-enhancing effects of temporary hyperoxia observed in vivo [8,19] by exposing cells to a short period of hyperoxia during treatment, following chronic culture under physioxia ( Figs. 1 and 2).…”

“…1A): (1) "physioxia", where cells were cultured and treated under 2% O 2 ; (2) "hyperoxia", where cells were cultured and treated under air (18.6% O 2 ); and (3) "physioxia + temporary hyperoxia", where cells were cultured under 2% O 2 and transiently exposed to air during treatment. This latter condition was included in an attempt to recapitulate observations made in vivo [8,19], where increased O 2 significantly improved photodynamic treatment efficacy. Thus, we investigated whether epidermoid carcinoma cells chronically cultured under the standard hyperoxic (18.6% O 2 ) cell culture conditions were less susceptible to oxidative stress-induced cell death, compared to those cultured under physioxia (2% O 2 ).…”

The effects of protoporphyrin IX-induced photodynamic therapy with and without iron chelation on human squamous carcinoma cells cultured under normoxic, hypoxic and hyperoxic conditions

“…Previous methods to potentially enhance the mechanism of action of PDT through oxygen manipulation have included the use of light dose fractionation [8], inhalation of carbogen or 100% normobaric oxygen (NBO) [9] or being subjected to hyperbaric oxygen (HBO) [9,10].…”

Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy

“…The evidence to date suggests if oxygen levels can be maintained and/or increased prior to, during or after PDT [5] then the efficacy of PDT might be improved. A number of direct and indirect methods have been investigated to improve tissue oxygenation and potentially allow reoxygenation of the tumor including; hyperthermia [11], normobaric oxygen (NBO), oxygen multistep therapy, hyperbaric oxygen (HBO) [12], perfluorocarbons [13], light dose fractionation [14,15] and lowering of the light fluence rate [16].…”