These data show for the first time that PROB can provide complete protection against ADR cardiomyopathy without interfering with antitumor properties of the drug. This protective effect of PROB may be related to the maintenance of the antioxidant status of the heart.
In order to determine whether host factors may contribute to the generation of tumor heterogeneity, the phenotypic stability of cells from a cloned tumor was examined during proliferation in tissue culture and in the syngeneic host. Growth of this cloned tumor was initiated both in vivo and in vitro, and the tumor populations were sampled at different time intervals by subcloning. The susceptibility of these tumor subclones to the cytotoxic action of natural antibodies and complement was used as a marker of their membrane phenotype. The extent of phenotypic variation of the clones in one sample was considered to be a measure of tumor heterogeneity. Following these procedures, we observed that a clone of the L5178Y murine lymphoma maintained its homogeneity during 5 months of in vitro culture. In contrast, a single passage of the same tumor clone for 3 1/2 weeks or 3 months in the syngeneic host resulted in the generation of a population of cells exhibiting a significant increase in heterogeneity. This relative instability of tumor phenotype in vivo suggests that the host milieu may allow the generation of tumor heterogeneity. Genetic or epigenetic mechanism(s) may be involved although the high frequency of new phenotypes argues against a role for somatic mutation.
The present study, which was designed to further characterize the "natural" T-independent rejection of syngenetic tumours (Greenberg and Greene, 1976), has revealed the following points: (1) no detectable DBA/2 NK cell activity was demonstrated against the syngeneic tumour lines studied, and these tumours were indensitive to NK cells from high-activity strains; (2) in addition the tumour frequencies in old and young mice receiving small tumour inocula were identical, in contrast with the reported decline in NK cell activity with age, suggesting that the surveillance of small inocula of these tumours was NK-cell-independent; (3) injection of silica intraperitoneally enhanced the frequency of tumours in normal and immunodeficient AT x BM mice, suggesting that the rejection mechanism was macrophage-dependent; (4) the effects of silica injection were maximal if administered 3 days prior to tumour injection, indicating that the period of time in which the rejection mechanism must act was very limited; (5) silica markedly decreased the survival of AKR mice dying of spontaneous tumours, providing evidence that the effect of this agent was not limited to model systems but would influence the appearance of spontaneous tumours; (6) reticuloendothelial stimulants such as mycobacterium butyricum and proteose peptone decreased the tumour frequency of small tumour inocula, indicating that the effector mechanism can be stimulated; and (7) soluble tumour antigen enhanced the tumour frequency in normal and immunodeficient mice, suggesting that the specific receptor molecule of the surveillance mechanism was not thymus-dependent.
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