IN a previous paper (Cohen and Cohen, 1956), it was shown that a significant radiosensitization of established C3H mammary tumour isografts could be induced by means of a second inoculation of the hosts with radiation-attenuated tumour fragments prior to treatment. It was noted at the time that the best results were obtained with the largest attenuation dose used (5000 r) provided the attenuated inoculum was given after implantation of the unmodified tumour graft, and the treatment of the established growth followed at least two weeks after inoculation of the attenuated material. Some questions concerning the optimal attenuation procedure, the possibility of increasing the effect by "booster" inocula, and the specificity of the sensitizing tissue, were not fully investigated. The following series of experiments were consequently designed to elucidate these points. MATERIALS AND METHODS Experimental designYoung adult male mice of the C3H/Cg strain were used as tumour recipients in all experiments. In order to maintain as uniform a tumour source as possible, a single autogenous mammary adenocarcinoma, arising in a female of the strain, was serially transplanted for ten generations in a group of mice who constituted a pool of tumour donors for all the experimental groups.Each of 149 recipient experimental mice was inoculated subcutaneously in the right axillary area with a fragment of the tumour introduced with a trocar and cannula. When the isografts became palpable (about 2 or 3 weeks later), the second, or attentuated, inoculum was given subcutaneously into the left flank. The animals were divided, according to the type of second inoculum received, into the 12 experimental categories listed in Table I. In two groups, attenuated tumour inocula were prepared from isografts minced with a fine scissors and irradiated with 7000 r and 10,000 r respectively, in a plastic welled slide immediately before implantation. At these dose levels there were no "takes" of any of the irradiated tumour implants.A further two groups were given repeated "booster" inocula of additional tumour fragments attenuated at the two dose levels. In addition to the first attenuated implant given about three weeks before treatment of the tumour in situ, the mice were again inoculated one week before, three weeks after treatment, and at monthly intervals thereafter.In another category, tumour fragments were irradiated with 7000 r and emulsified in an equal volume of Freund's adjuvant complete with M. butyricum suspension (" Bacto-Adjuvant ", Difco) prior to inoculation.
IN a previous experiment (Cohen and Cohen, 1953) the LD50 for the treatment of the C3H adenocarcinoma in situ was found to be 5700 (+ 140) r. It was considered that this quantity was not necessarily a fixed property of the tumour, but was probably dependent upon the state of the host. Both spontaneous and radiation-induced regression of tumours are known to be associated with stromal and lymphoid reactions or similar manifestations of a resistance mechanism in the host (Murphy, 1926). It has been shown that total body radiation can affect the host to such an extent that spontaneous regression of a homoplast can be reversed (Cohen and Cohen, 1951) and even genetic resistance to a heterologous implant can be overcome (Clemmesen, 1938). It seemed likely, therefore, that total body irradiation would also tend to prevent radiation-induced regression of tumours, and might consequently modify the curative dose for treatment in situ. Accordingly, in the following experiment, the quantitative effect of total body radiation of the host on the radiocurability of the C3H mammary tumour is demonstrated. MATERIALS AND METHODS.Animals.The mice used in this investigation are a registered subline, designated C3H/Cg, originating from a high mammary tumour strain C3H/Jax, which has been maintained in this laboratory since 1951. The technique of homoiotransplantation and irradiation of tumour homoplasts in situ is identical with that reported in a previous paper (Cohen and Cohen, 1953). Radiation factors.The total body dose was given with 240 kV., 1 mm. Cu + 1 mm. Al filter, HVL 1-5 mm. Cu, FSD 50 cm.; the mice being treated en masse in a shallow cardboard box measuring 20 x 20 x 3 cm., at a surface dose rate of 50 r/min. At this quality of radiation, the dosage distribution throughout the body of each mouse is practically homogeneous.Experimental design.In a recent paper (Kaplan and Brown, 1952) it was shown that a maximal depression of host resistance to tumour induction with a minimal mortality of mice could be obtained by total body radiation delivered in 4 fractions at four-
IN a previous communication (Cohen and Cohen, 1954b) it was noted that tumours arising from viable grafts of the C3H mammary carcinoma, which had been attenuated by sublethal doses of radiation immediately before implantation, were found, when subsequently irradiated in situ, to have a significantly increased radiosensitivity. The radiosensitization did not appear to be due to any permanent change in the tumour, or to any local reaction in the tumour bed, but could be explained only on the basis of a subliminal systemic resistance mechanism, possibly in the nature of a circulating iso-antibody arising in the host. If this postulate is correct, it might be possible to enhance the radio-sensitivity of an established non-attenuated isograft by inoculation of the host with a suitably attenuated second implant. The present investigation demonstrates that induced radiosensitization of an isogenic tumour in inbred mice is feasible, and may possibly point the way to more efficient therapy of autogenous growths.The procedure is complicated by additional variables not encountered when the radiation-attenuated homografts themselves are treated. The attenuation doses can vary widely, and may include a higher dosage range where the irradiated inocula no longer "take ". One may also choose almost any interval between implantation of the unmodified tumour and the inoculation of the irradiated fragment. Further, the time between the dates of implantation of the attenuated inoculum and of the treatment in situ of the established tumour may vary widely. The present experiment, therefore, is designed firstly to explore the possibility of radiosensitization of an unmodified transplanted C3H mammary adenocarcinoma by means of an attenuated tumour inoculum, and secondly to seek effective combinations of timing and dosage factors for this type of procedure. MATERIALS AND METHODS Experimental designYoung adult male mice from the C3H/Cg substrain were used. Each received two inoculations: one consisting of fragments of an unmodified inoculum, that is the usual isogenic C3H mammary tumour homoplast, into the right flank, and the second an attenuated inoculum, tumour fragments irradiated in vitro prior to implantation, into the left flank. After a suitable period, depending on the experimental variables, the unmodified tumour was irradiated in situ using the standard procedure. It was considered that the following variables might affect
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