Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation

Abstract

The proportion of viable hypoxic cells in EMT6/St/lu tumours assayed 18 and 24 hours after a dose of misonidazole (1.2 mg/g), which killed 80–90% of the tumour cells, was reduced from 20% in the controls to 7% in the misonidazole treated mice. In other experiments, the radiation cell-survival curve of the RIF-1 tumour was assayed in both intradermal and intramuscular sites under both air-breathing and acutely hypoxic conditions. The slope of the survival curve of the intramuscular tumours irradiated under air-breathing conditions was significantly steeper than that of the same tumours growing intradermally (D0 values of 187 rad vs. 357 rad), or when the tumours were irradiated in either site under acutely hypoxic conditions (D0 = 375 rad). Both of these experimental observations are examined in the light of data from other sources, notably from the radiation response of hypoxic cells in spheroids and from observations made from tumours implanted between close, parallel mica sheets (“sandwich” tumours). It is concluded that these results, taken together with the other data, suggest that rodent tumours contain acutely hypoxic cells, as well as the classically described chronically hypoxic cells. It is argued further that, if (as appears to be the case) acutely hypoxic cells are produced by intermittent opening and closing of tumour blood vessels, then this process would provide a simple explanation for the rapid reoxygenation seen in several mouse tumours. Finally, it is pointed out that a consequence of the presence of acutely hypoxic cells in tumours is that they would largely frustrate attempts to radiosensitize tumours using either respiratory inhibitors or high pressure oxygen, or agents designed to selectively kill hypoxic tumour cells, since both of these methods would deal only with the chronically hypoxic cells.