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Reoxygenation and rehypoxiation in the SCCVII mouse tumor
1Department of Radiation Oncology, Stanford University School of Medicine, CA 94305-5468.
Purpose:
To test the hypothesis that, following preferential killing of tumor hypoxic cells, the fraction of hypoxic cells in the tumor will reestablish itself to pretreatment levels (rehypoxiation) with the same kinetics as for reoxygenation.
Methods And Materials:
Mouse squamous cell carcinoma VII (SCCVII) tumors were treated with a single dose of 10 Gy or a single dose of the bioreductive hypoxic cell cytotoxin, tirapazamine (SR 4233, 0.2 mmol/kg), which preferentially kills hypoxic cells within the tumor. Hypoxic fractions were determined by the paired survival curve technique using the in vivo-in vitro clonogenic assay 0-24 h after treatment.
Results:
Immediately after irradiation with 10 Gy, the hypoxic fraction of the tumors increased to 80% and rapidly returned to pretreatment levels 3-6 h later. Within 1 h of injecting tirapazamine, the hypoxic fraction fell to 0.57% (about 7% of pretreatment levels) and returned to pretreatment levels 3-5 h later.
Conclusion:
The return to pretreatment levels of hypoxia among tumor cells surviving a single dose of radiation (reoxygenation) and of the hypoxic cell toxin tirapazamine (rehypoxiation) was rapid and occurred with similar kinetics for the two processes. These data support the hypothesis that reoxygenation and rehypoxiation are different manifestations of the same phenomenon and result from fluctuating tumor blood flow which creates acute hypoxia.