Addition of a hypoxic cell selective cytotoxic agent (mitomycin C or porfiromycin) to Fluosol-DA/carbogen/radiation.
In an effort to develop effective combination treatments for use with radiation against solid tumors, the cytotoxic effects of the addition of mitomycin C or porfiromycin on treatment with Fluosol-DA/carbogen (95% O2/5% CO2) breathing and radiation in the FSaIIC tumor system were studied. In vitro mitomycin C and porfiromycin were both preferentially cytotoxic toward hypoxic FSaIIC cells. After in vivo exposure, however, the cytotoxicity of mitomycin C toward single cell tumor suspensions obtained from whole tumors was exponential over the dose range studied, but for porfiromycin a plateau in cell killing was observed. With Fluosol-DA/carbogen breathing and single dose radiation, addition of either mitomycin C or porfiromycin increased the tumor cell kill achieved at 5 Gy by approximately 1.2 and 1.0 logs, respectively. Less effect was seen with addition of the drugs at the 10 and 15 Gy radiation doses. In tumor growth delay experiments, the addition of either mitomycin C or porfiromycin to Fluosol-DA/carbogen breathing and radiation resulted in primarily an additive increase in tumor growth delay. The survival of Hoechst 33342 dye-selected tumor cell subpopulations indicated that Fluosol-DA/carbogen breathing increased the cytotoxicity of radiation (10 Gy) more in the bright cell subpopulation (4-fold) than in the dim cell subpopulation (2-fold) resulting in an overall 4-fold sparing of the dim subpopulation. Mitomycin C and porfiromycin were both more toxic toward the dim cell subpopulations. Addition of mitomycin C or porfiromycin to Fluosol-DA/carbogen breathing and radiation (10 Gy) resulted in a primarily additive effect of the drugs and radiation killing in both tumor cell subpopulations. Thus, with mitomycin C/Fluosol-DA/carbogen and radiation there was a 2-fold sparing of dim cells and with porfiromycin in the combined treatment a 1.6-fold sparing of the dim cell population. Our results indicate that treatment strategies directed against both oxic and hypoxic tumor subpopulations can markedly increase the tumor cell kill achieved by radiation.
Holden
S A
SA
Dana-Farber Cancer Institute, Boston, MA 02115.
Herman
T S
TS
Teicher
B A
BA
D000818:Animals; D002245:Carbon Dioxide; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations / Q000494:pharmacology; D005466:Fluorocarbons / Q000494:pharmacology*; D006895:Hydroxyethyl Starch Derivatives; D008297:Male; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000473:pathology*; D010100:Oxygen; D011160:Porfiromycin / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D005466:Fluorocarbons; D006895:Hydroxyethyl Starch Derivatives; D008937:Mitomycins; D011838:Radiation-Sensitizing Agents; D002245:Carbon Dioxide; D016685:Mitomycin; C017323:glucose, glycerol, hydroxyethyl starch, perfluorodecalin, perfluorotripropylamine, pluronic F-68, salts, yolk phospholipids drug combination; C011700:carbogen; D011160:Porfiromycin; D010100:Oxygen