Comparison of the enhancement of tumor responses to fractionated irradiation by SR 4233 (tirapazamine) and by nicotinamide with carbogen.
OBJECTIVE
This study was undertaken to compare in a fractionated regimen, with clinically relevant radiation doses, two radiation response modifiers that function by different mechanisms: SR 4233, a bioreductive agent toxic to hypoxic cells, and nicotinamide with carbogen, a combination that has been shown to improve tumor oxygenation.


METHODS
Cell survival assays were used to examine the response of three different tumors: KHT, RIF-1 and SCCVII/St in C3H/Km mice. Regrowth delay studies were also performed with the RIF-1 tumor. A fractionated irradiation schedule, consisting of twice daily 2.5 Gy treatments was investigated with and without drug pretreatment. SR 4233 was given IP at 0.12 mmol/kg one half hour before each irradiation. Nicotinamide (250, 500, 1000 mg/kg) was given IP 1 h before each irradiation with carbogen exposure 5 min prior to and during the irradiation.


RESULTS
Both treatment strategies enhanced the response of all three tumors to the fractionated radiation regimen. However, for two of the tumors (KHT and SCCVII), SR 4233 produced a significantly greater enhancement than did the combination of nicotinamide + carbogen. For the RIF-1 tumor (which has the lowest hypoxic fraction of the three), the response was comparable for the two modalities. For nicotinamide + carbogen, there was no significant change in the radiation enhancement at nicotinamide doses between 250 and 1000 mg/kg.


CONCLUSIONS
Adding the bioreductive cytotoxin SR 4233 or nicotinamide + carbogen to fractionated irradiation enhances the response of the three transplanted tumors used in this study to fractionated irradiation. The radiation enhancement was significantly greater, however, for SR 4233 for two of the tumors with comparable results in the third. The data are consistent with the prediction that killing tumor hypoxic cells can produce a similar or greater enhancement of the efficacy of fractionated radiation in enhancing tumor response than either oxygenating or radiosensitizing these cells.
Dorie
M J
MJ
Department of Radiation Oncology, Stanford University School of Medicine, CA 94305.
Menke
D
D
Brown
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002245:Carbon Dioxide / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004338:Drug Combinations; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D009536:Niacinamide / Q000627:therapeutic use*; D010100:Oxygen / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000077704:Tirapazamine; D014227:Triazines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004338:Drug Combinations; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D002245:Carbon Dioxide; D000077704:Tirapazamine; D009536:Niacinamide; C011700:carbogen; D010100:Oxygen