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Combined Modality Therapy with Bleomycin, Hyperthermia, and Radiation¹

Dana-Farber Cancer Institute [B. A. T., T. S. H., S. A. H.] and the Joint Center for Radiation Therapy [T. S. H.], Boston, Massachusetts 02115

In an attempt to develop better combination therapies for use with local radiation, the interaction between bleomycin and hyperthermia ± radiation was studied in the FSaIIC tumor system. In cells exposed in vitro to bleomycin at 37°C and at pH 7.40, the drug was substantially more toxic toward normally oxygenated than hypoxic cells. At hyperthermic temperatures (42° or 43°C), however, the differential killing between the normally oxygenated and hypoxic cells disappeared and bleomycin became significantly more toxic. Exposure to bleomycin at pH 6.45 did not substantially alter the cytotoxicity of the drug at 42° or 43°C. In tumor growth delay experiments, combining bleomycin, hyperthermia, and radiation induced long delays, and the more successful sequences were bleomycinradiationhyperthermia or bleomycinhyperthermiaradiation. If radiation was given prior to drug and hyperthermia, however, the sequence was significantly less effective. In tumor excision experiments performed 24 h after treatment, increasing doses of bleomycin produced a shallow, log-linear increase in tumor cell kill at 37°C, but bleomycin followed by hyperthermia (43°C, 30 min) led to about 1 log more cell killing. Administration of bleomycin just prior to treatment with a single dose of radiation was cytotoxically additive. In this assay the most effective trimodality treatment sequence was bleomycinhyperthermiaradiation.

In tumor subpopulations defined by Hoechst 33342 dye staining, bleomycin at 37°C was about two-fold more toxic toward the bright (presumably well-oxygenated) cells than toward the dim (presumably hypoxic) cell subpopulation. The addition of hyperthermia following bleomycin produced nearly a log more tumor cell killing in both the bright and dim tumor cells. The combination of bleomycin followed by hyperthermia and then radiation was at least additive in the bright cells and caused a large cell kill, but, in comparison, there was marked sparing of the dim cells. These results indicate that treatment with bleomycin and hyperthermia in conjunction with radiation can add substantially to tumor cell killing. This combination is significantly less effective in the hypoxic than oxic tumor regions, however, in spite of in vitro data which demonstrate that the cytotoxicity of bleomycin at hyperthermic temperatures is not oxygen-dependent.

¹ This work was supported by NCI Grants PO1-38493 [B. A. T.] and RO1-36508 [B. A. T.] and grants from the Fuller Fund [T. S. H] and New England Deaconess Hospital [T. S. H.].

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Received 6/23/88. Accepted 8/11/88.