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Reduced Tumor Oxygenation by Treatment with Vinblastine¹

Department of Tumor Biology, Institute of Oncology Ljubljana, Ljubljana, Slovenia [G. S., M. C., M. A.]; Jozef Stefan Institute, Ljubljana, Slovenia [M. K., M. S., K. B.]; University of Ljubljana, Veterinary Faculty, Ljubljana, Slovenia [T. I.]; and Department of Radiology, Dartmouth Medical School, Electron Paramagnetic Resonance Center for the Study of Viable Biological Systems, Hanover, New Hampshire 03755 [H. M. S.]

Vinblastine (VLB) previously has been shown to perturb tumor blood flow, but the effect of these perturbations on tissue oxygenation is not known. The recent development of electron paramagnetic resonance (EPR) oximetry now has made it feasible to measure the effects of changes of perfusion on the pO₂ in tumors and normal tissues as a function of time and dose. We measured changes in tumor perfusion by Patent blue staining, tumor blood volume and microvascular permeability by contrast-enhanced magnetic resonance imaging, and tumor oxygenation by EPR in s.c. SA-1 murine tumors. We found that treatment with VLB induced dose-dependent reduction in tumor perfusion. One hour after i.p. treatment of mice with 2.5 mg/kg VLB, tumor perfusion was reduced to 20% of the pretreatment value and returned to close to original values within 48 h. A transient tumor blood flow-modifying effect of VLB was demonstrated also by contrast-enhanced magnetic resonance imaging; reduction of tumor blood volume and microvascular permeability was found. Reduced tumor oxygenation was found as measured by EPR oximetry, with the same time course of changes in tumor blood flow. Tumor oxygenation was reduced to 50% of pretreatment value 1 h after the treatment with 2.5 mg/kg VLB and returned to pretreatment levels within 24 h after the treatment. Although the directions of the changes in perfusion and oxygenation were similar, they were quantitatively different. Reduction in oxygenation of normal tissues, muscle, and subcutis also occurred but was smaller and returned to pretreatment values more quickly compared to the changes induced in the tumors. In conclusion, the present study demonstrates that VLB causes a profound reduction in tumor blood flow and oxygenation, which may have implications in controlling side effects of therapy and the planning of combined treatment with VLB, either with other chemotherapeutic drugs or with radiotherapy.

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