Implications of a pre-existing tumor hypoxic fraction on photodynamic therapy.
The presence of oxygen in tissue is a requirement for photodynamic therapy (PDT)-induced destruction of solid tumors, otherwise no cell death occurs. Since many tumors have been shown to have significant populations of hypoxic cells, it is of clinical interest to determine if pre-existing tumor hypoxia limits phototherapy. This question was examined using RIF tumors where tumor response to PDT of completely oxygenated tumors was compared to tumors with an induced hypoxic fraction. Tumor hypoxia was induced by using vasoactive drugs (epinephrine, chlorpromazine, or isoproterenol), given 30 min prior to PDT, or by a surgical method. PDT consisted of 5 mg/kg Photofrin II ip 24 hr prior to treatment and 135 J/cm2 630-nm light. The administration of the various vasoactive agents induced hypoxic fractions of 2.2 to 10%. The surgical method induced hypoxic fractions of 35%. Tumor response and cure in animals given vasoactive agents did not differ from controls, suggesting that low levels of pre-existing tumor hypoxia do not limit photodynamic therapy in this tumor model. Animals with tumors made hypoxic by a surgical method showed significantly reduced tumor response to PDT. Only 14% of these animals had tumors which became flat and necrotic by the day following PDT, compared to nearly 100% for animals given vasoactive drugs or controls. Furthermore, no tumor cure was observed in animals treated by this method. The higher level of tumor hypoxia in these animals likely represents one point where large proportions of PDT-resistant cells can survive after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Fingar
V H
VH
Department of Surgical Oncology, James Graham Brown Cancer Center, University of Louisville, Kentucky 40292.
Wieman
T J
TJ
Park
Y J
YJ
Henderson
B W
BW
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D019793:Fluorescein; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D010778:Photochemotherapy
D005452:Fluoresceins; D005456:Fluorescent Dyes; D017323:Dihematoporphyrin Ether; D007545:Isoproterenol; D019793:Fluorescein; D002746:Chlorpromazine; D004837:Epinephrine