P.W. Sheldon

Skin reactions in mice after multifraction x-irradiation.

SummaryFractionated doses of 240 kV X-rays were given to one hind leg of mice, and skin reactions were recorded up to 5 weeks after the last dose. The following schedules of irradiation were used: 15 equal fractions in 18 days (15F/18d), 9F/18d, 9F/10d, 5F/9d, 5F/4d, 3F/4d, 2F/2d and single doses. The dose required to produce a given average skin reaction over the period 10 to 32 days, or a corresponding period after multifraction doses, increased steadily with time and fraction number; except for the 9F/10d schedule which produced reactions significantly less than would be expected from any simple sequence. The results are discussed in comparison with other experiments on skin. After allowing for concurrent proliferation, a dose–response curve was derived which had a Dq of 550 rads and a straight portion for doses above 1200 rads. The ratio of initial to final slopes was approximately 0·4 and this indicated the ratio of irreparable to reparable X-ray injury in the skin.

Optimum fractionation of the c3h mouse mammary carcinoma using x-rays, the hypoxic-cell radiosensitizer ro-07-0582, or fast neutrons.

Abstract Experiments extending over several years have now been completed in which local control of mammary tumors in C3H mice was compared with acute skin reactions in other mice for a number of fractionated X-ray and fast neutron schedules. This paper presents the latest results, summarizes the previously published results, and discusses the pattern which has now emerged. Two types of fractionated treatment have been investigated: short overall times of up to 4 days and longer overall times of 9–18 days. The effectiveness of each schedule was estimated by comparing the local tumor control that could be achieved for a given skin reaction. In the short treatment schedules, the extent of tumor control was very variable, ranging from poor to good. It was critically dependent on fraction size and on the interval between fractions in a way that was consistent with reozygenation in the tumor bring the crucial factor. In the longer treatment schedules, fraction size and interval were not so critical end overall time was the governing factor; too long overall dam yielded poor results because proliferation in the tumor was faster then in skin. In the short, variable, type of treatment it was shown that poor results using X-rays could be improved, to about the same level as the best X-ray results, by using either the specific hypoxic-cell radiosensitizing drug Ro-07-0582 with X-rays, or by using cyclotron-produced fast neutrons. These observations support the concept of hypoxia and reoxygenation being the crucial factors in short treatment schedules.

Radiosensitization by Misonidazole (Ro 07-0582) The Importance of Timing and Tumor Concentration of Sensitizer

The radiosensitizing effect of misonidazole (Ro 07-0582) is presented for four types of mouse tumor. The interval between administration of the drug and irradiation has been found to have a large effect on the extent to which hypoxic tumor cells are sensitized. The optimal time for irradiation differed in the different tumors and ranged from 15 to 120 min. This delayed effectiveness probably relates to the time required for diffusion of the drug to the critical hypoxic regions and for its concentration in those regions to reach a maximum. Drug concentrations have been measured in whole blood and in the tumors using gas-liquid chromatography. The tumor concentrations ranged from 20 to 70% of the blood level in the four tumors; in man it was 40-107%. The in vivo radiosensitizing effect of the drug at these measured concentrations in tumors is similar to that achieved in vitro. The apparent loss in radiosensitizer effectiveness in mouse tumors in vivo relative to in vitro results is thus due to the lower con...

Optimum fractionation in X-ray treatment of C3H mouse mammary tumours.

Abstract The doses required to control 50 per cent of tumours at 150 days after irradiation were determined for eight fractionated X-ray schedules. The tumours were first-generation transplants from spontaneous mammary tumours in C3H/ He mice. The schedules were: single doses, 5, 9 or 15 fractions given daily excluding weekends, and 2, 3, 5 or 9 fractions at the two-day interval known to be optimal for reoxygenation in these tumours after a priming dose of 1,500 rads. For comparison, skin reactions on the feet of albino mice were determined, using the same fractionation schedules, in order to plot the tumour control probability (TCP) against skin reactions for corresponding schedules. Two optimum schedules were found which gave maximum local control of tumours for the lowest skin reaction: nine fractions in ten days (9F/10d) and 5F/9d. The treatments given in shorter overall times were fairly good if the two-day intervals were used but were poor for “daily” doses. Both schedules employing overall times of...

The effect of anesthetics on the radiosensitivity of a murine tumor.

The effect of four anesthetics on the single dose of x rays required to locally control 50% of implanted MT tumors was investigated. Compared with unanesthetized animals, no change in radiosensitivity was observed if mice were irradiated under either tribromoethanol or fentanyl-fluanisone-diazepam anesthesia. However, a small but significant degree of radioprotection was observed under chloral hydrate or pentobarbital anesthesia. Hypothermia or increased hypoxia are considered unlikely mechanisms for the protection, a direct chemical action being most probable. The preferred method for immobilizing the mice in order to locally irradiate the tumors was by simple physical restraint (with care taken to minimize physiological stress). However, if anesthesia was a necessity, the present work suggests that for the MT tumor at least the nonprotecting tribromoethanol and fentanyl-fluanisone-diazepam are preferable to the protecting chloral hydrate and pentobarbital. Tribromoethanol is preferable to fetanyl-fluanisone-diazepam in that it produces a smaller drop in temperature. However, it is only a short-acting anesthetic, and prolongation of the state of anesthesia by repeated doses simply prolongs the temperature decline so that there may be no real benefit over fentanyl-fluanisone-diazepam.

Radiosensitization of C3H mouse mammary tumours using fractionated doses of X rays with the drug Ro-07–0582

Three fractionated X-ray schedules were used, with and without the electron-affinic radiosensitizer of hypoxic cells, Ro-07-0582, to determine the local control of first-generation transplants of spontaneous mammary tumours in C3H mice. Three or five fractions were given in either four or nine days overall time. The results were compared with acute skin reactions in other mice caused by the same treatment schedules. For a given skin reaction, the local control of tumours varied widely, from good to bad, when different X-ray only schedules were used. All three schedules using Ro-07-0582 however yielded good results. It appears that the use of the hypoxic-cell radiosensitizer took the unreliability out of these short fractionated treatments.

Hypoxic cell sensitlzation by misonidazole in vivo and in vitro

The effect of misonidazole (Ro 07–0582, Roche Products Ltd., Welwyn Garden City, Herts.) as a radiosensitizer of hypoxic cells has been reported for several cell lines in vitro and for many tumour lines grown in vivo (Adams et al., 1976a). However, there have been no direct comparisons of the effects of this drug in vivo and in vitro because of a lack of data on the intra-tumour concentration of the drug. Recently Flockhart et al. (1977) have developed a method to measure the concentration of unchanged, misonidazole in tumours by gas-liquid chromatography. This article reports measurements of the ability of misonidazole to sensitize hypoxic cells in four different tumours to radiation as a function of its measured concentration in the tumours at the time of irradiation. These results are compared with those previously obtained for cells in culture.