Summary.-Skin reactions on irradiated mouse feet were used to measure the radiosensitization of normal tissues by misonidazole (MISO). Fractionation schedules of 1, 2, 5 and 10 daily doses of X-rays were combined with either 100 mg/kg or 670 mg/kg MISO. When unanaesthetized mice were irradiated in air, significant sensitization was observed with both the high and low drug doses, in all fractionation schedules. There was no decrease in sensitization with fractionation, even using fractions as small as 5 Gy. This indicates that many of the cells in mouse skin may be marginally hypoxic, and that sensitization at low doses is possible.Irradiation in 02 without MISO rendered the skin more sensitive to X-rays than in air. MISO given 30 min before single doses of radiation further sensitized the skin, but for 10 fractions in 02 no MISO sensitization was detected.There was little evidence for cytotoxic killing in skin by MISO. Repair of radiation damage was slightly reduced when MISO was present, during or after irradiation.

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Summary A method for estimating both structural and functional vascular volumes in murine sarcomas is described. Intact vessels were demonstrated by the presence of laminin, a basement membrane-associated antigen, using an immunofluorescent technique. and functional vessels in the same sample by prior injection with the DNA binding dye Hoechst 33342. No significant vascular effects were seen after melphalan but a very pronounced decrease in both functional and structural vascular volume was seen after MISO. Combined chemotherapy of a murine sarcoma with melphalan and MISO induced a rapid decrease in the functional vascular volume, anid there was a resumption of blood flow prior to measurable regrowth. The fully regrown tumour retained the vascular characteristics of untreated tumours of similar size.The observed effects of ionizing radiation on tumour growth are attributed by some authors to a direct cytotoxic action on tumour cells, as well as an indirect cytotoxic action, resulting from vascular and stromal damage (Thomlinson & Craddock, 1966;Mattson & Peterson, 1979 Song, 1984). As occlusion of the vasculature can alone lead to tumour control or cure (Denekamp et al., 1983), the vascular component of any form of therapy must not be underestimated; indeed the vasculature itself may represent an important target for therapy (Denekamp, 1984). In contrast to radiation and hyperthermia, however, little is known about the possible contribution of a vascular component in chemotherapy; in general the effects are considered the result of direct tumour cell kill.In this study we have examined the effects of the alkylating agent melphalan on the vasculature of a murine sarcoma when used alone or in combination with the radiosensitizer Misonidazole (MISO). MISO is known to potentiate the effects of melphalan. The origins of this phenomenon, known as 'chemosensitization', are not fully understood. Among the possible mechanisms that have been proposed are: that MISO is directly cytotoxic to hypoxic cells, alters the pharmacokinetics of the cytotoxic drugs, interferes with the repair of potentially lethal damage, or depletes intracellular thiols; (For reviews see McNally, 1982;Millar, 1982;Siemann, 1982;. The present study was carried out to determine whether a vascular component could be attributed to the potentiation of melphalan cytotoxicity by MISO. Although many methods exist for studying structural and functional parameters of normal tissues and tumours, in general these methods do not distinguish patent vessels from those which may be temporarily, or permanently, non functional. We utilize here a method whereby, in the same tumour sample, structural and functional information can be obtained using a morphometric technique. The method relies upon the identification of blood vessels by the immunolluorescent demonstration of the glycoprotein laminin, present in the blood vessel walls (Timpl et al., 1979). This structural marker was used in parallel with a functional fluorescent marker, bis-benzamide Hoechst 33342, inj...

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Summary The effect of melphalan alone or combined with various schedules of misonidazole (MISO) has been tested on a murine fibrosarcoma. The tumoricidal effect has been determined using the growth delay assay. Large single doses (500-1000mg kg-1) of MISO enhanced the anti-tumour effect of melphalan, especially at high melphalan doses. This was accompanied by a drop in body and tumour temperature and an increase in the melphalan half-life. The MISO-induced hypothermia was prevented in one experiment by keeping the mice in an ambient temperature of 35°C for 3 h. This reduced the exposure to melphalan but did not diminish the cytotoxic effect of the drug combination.Chronic administration of MISO for an 8h period gave no enhancement of melphalan damage, whether melphalan was given half-way through or at the end of the period of dosing. It seems that a threshold tumour concentration of MISO, in excess of 70 pg g-, is needed for enhancement of melphalan cytotoxicity; prolonged exposures to very low doses are ineffective.