Abstract
There is now evidence that several classes of nitro compounds which have been used as radiosensitizers also function as cytotoxic agents specific for hypoxic cells. The 2-nitroimidazole, Ro-07-0582, (1-(2-nitroimidazol-1-yl)-3-methoxy-2-propanol) is a compound of this type, and its effectiveness as a cytotoxic agent is dependent on drug concentration, contact time and temperature. In vitro, Ro-07-0582 in air at 37 degrees C does not cause loss of cell viability at concentrations up to 2 mM, even when in contact for several days. In contrast, hypoxic cells do not tolerate much lower concentrations of drugs, even if the contact time is only a few hours. When the temperature is raised above 37 degrees C, there is a pronounced increase in the slope of the survival curves; for example, at 41 degrees C (for 1 mM Ro-07-0582, (200 microng/ml), the slope changes by a factor of 2-0 relative to that for 37 degrees C. For cells in air at 41 degrees C, as at 37 degrees C, there is no toxic effect at the concentration of drug tested. In the absence of drug, there is no cytotoxic effect of hyperthermia alone under these conditions. These results are discussed in terms of Arrhenius parameters.
Highlights
Summary.-There is evidence that several classes of nitro compounds which have been used as radiosensitizers function as cytotoxic agents specific for hypoxic cells
Drugs toxic towards hypoxic cells could have potential value as cancer chemotherapy agents, when used in combination with agents which are specific for cycling cells
With respect to Ro-07-0582, serum levels at least as large as 05 mm can be achieved in man with an apparent halflife of about 12 h (Gray et al, 1976). It would be inferred from the in vitro data at 370C, that tumours in contact with drug concentrations of this order for several hours would undergo an appreciable reduction in hypoxic cell content
Summary
Summary.-There is evidence that several classes of nitro compounds which have been used as radiosensitizers function as cytotoxic agents specific for hypoxic cells. The 2-nitroimidazole, Ro-07-0582, (1-(2-nitroimidazol-1-yl)-3methoxy-2-propanol) is a compound of this type, and its effectiveness as a cytotoxic agent is dependent on drug concentration, contact time and temperature. There are many compounds of widely relative to well-oxygenated cells (Sutherdifferent chemical structure known to be land, 1974; Hall and Roizin-Towle, 1975; very efficient radiosensitizers in vitro, Foster et al, 1976; Mohindra and Rauth, most of these have little or no 1976), and this has led to consideration of effect in vivo, due mainly to their meta- their possible future role in cancer chemobolic instability. 2 of which, metroni- the mechanism of this effect, we have dazole, a 5-nitroimidazole This paper describes the effect of temperature in the range 25° to 41°C on the cytotoxic effect of Ro-07-0582 on hypoxic Chinese hamster V79 cells in vitro
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