Hypoxic Sensitizers: Radiobiological Studies at the Cellular Level

Summary.-The tumour used, designated MT1, is a more radiosensitive form of the anaplastic MT tumour previously described. No explanation for the increased radiosensitivity was found, but it was shown not to be due to infection or to a change in immunological status, growth rate or histology. The sensitivity has remained constant throughout the present work.No cytotoxicity in the tumour was observed when 1 mg/g body weight of Ro-07-0582 was injected immediately after a single dose of X-rays; indeed a small protective effect was seen.A radiosensitization enhancement of 1P5 was achieved with a relatively low drug dose of Ro-07-0582 in a 5F/4d fractionated regime.The interval between the injection of a low dose of Ro-07-0582 and the start of irradiation was found to be critical, the optimum interval being 45-60 min.The subsequent incidence of distant metastases was not increased by the use of Ro-07-0582 at the time of "primary" tumour irradiation.

Section: Tumour Changementioning

confidence: 99%

Further investigations of the effects of the hypoxic-cell radiosensitizer, Ro-07-0582, on local control of a mouse tumour

Sheldon¹,

Hill²

1977

“…The proportion of welloxygenated to hypoxic cells in the tumour will also influence the observed sensitizer enhancement ratio (SER') since at low radiation doses the tumour response is dominated by the oxic rather than the hypoxic cells (Denekamp & Harris, 1975;Denekamp et al, 1977). In addition to the radiosensitizing action of MISO, there is a direct cytotoxic action, which is also specific for hypoxic cells (Sutherland, 1974;Hall & Roizin-Towle, 1975). The magnitude of this effect in human tumours is difficult to predict, but it has been shown to be small compared with the radiosensitization in both mouse and man (Denekamp, 1978;Denekamp & McNally, 1978).…”

mentioning

confidence: 99%

Is tumour radiosensitization by misonidazole a general phenomenon?

Denekamp¹,

Hirst²,

Stewart³

et al. 1980

Summary.-The response of 14 mouse tumour sub-lines to the radiosensitizing action of a large single dose of misonidazole (MISO) has been assessed by regrowth delay. In 13 of these, significant enhancement of radiation effect occurred under ambient conditions, indicating sensitization of naturally hypoxic cells. The enhancement observed (SER') varied with the radiation dose, as would be predicted for a mixed oxic/hypoxic cell population. The maximum SER' in these 13 tumours did not depend on histology or regrowth rate.The 14th tumour, a slow-growing sarcoma, was not sensitized under ambient conditions, but showed marked sensitization when clamped to produce acutely hypoxic cells. This is consistent with no hypoxic cells occurring naturally in a sarcoma with a slow rate of growth. Faster-growing variants of this tumour showed radiosensitization under ambient conditions.The slow-growing carcinoma, RH, however, appears to contain hypoxic cells and did show sensitization. The cytotoxic action of MIS0 was compared with the radiosensitization by administering it after irradiation in 8 of the tumour lines. In 2 tumours no cytotoxicity was observed. In the rest cytotoxicity was significant, but much smaller than the sensitization observed when MISO was administered before irradiation.These regrowth-delay data have been used to calculate hypoxic fractions in 3 ways.Estimates of hypoxic fraction ranged from <0-1% in the slow sarcoma to >30% in several tumours. There is considerable variation in the estimate, according to the technique used.

“…addition to the armamentarium of the radiotherapist because it sensitizes hypoxic cells which are otherwise relatively resistant to X-rays and may limit the radiocurability of some human tumours (Asquith et al, 1974;Denekamp and Harris, 1975;Thomlinson and Gray, 1955). MIS may also find a place in multidrug chemotherapy regimens, because it, is also cytotoxic towards hypoxic cells (Hall et al, 1977, Hall andRoizin-Towle, 1975;Stratford and Adams, 1977). These undoubted benefits must be weighed against the possibility that the nitroimidazoles are potent carcinogens.…”

Section: Methodsmentioning

confidence: 99%

Oncogenic transformation in vitro by the hypoxic cell sensitizer misonidazole

Miller¹,

Hall²

1978

Summary.-The hypoxic cell sensitizer Misonidazole (Ro-07-0582) induces oncogenic transformations in the C3H/1OTI mouse embryo cell line cultured in vitro. A drug concentration of 04 mM applied to aerated cells for 3 or 6 days results in a transformation rate comparable to that observed following an X-ray dose of 1 Gray. A higher drug concentration of 6 0 mM is equivalent to 4 Gy. The combination of Misonidazole and X-rays produces a significant increase in the frequency of transformation over either drug or radiation alone, but the data are equivocal on the question of additivity vs synergism.