Experimental studies of the effect of cancer chemotherapy on cellular immunity and its modification.
thesisposted on 2015-11-19, 08:52 authored by Ian Fraser
The experimental evidence for an immune response to cancer has been reviewed, and the effects of cytotoxic chemotherapy shown to affect nearly all of its aspects. Augmentation of the immune response (immunotherapy) has been discussed in the context of several important agents. It is argued that in advanced cancers the tumour burden is too great for significant benefit from immunotherapy. However in patients with 'minimal residual disease' there is little evidence for impairment of immune responses. When such patients receive adjuvant chemotherapy the number of residual cancer cells is further reduced, but the patient's immunological ability to complete their elimination is seriuosly impaired by the treatment. This situation may be a most suitable opportunity to achieve benefit from immunotherapy, and this study concerns attempts to identify means of achieving this. The work is concentrated on one major arm of the immune response, both in normal rats and some in whom breast cancers were induced. T lymphocyte function was measured in rats by an in vivo (DTH response) and an in vitro (PHA blastogenesis) method. Clear depression was seen following one injection of cyclophosphamide or 5 fluorouracil (5FU) in both normal and tumour bearing animals, and this lasted for at least one month (PHA). The rebound overshoot phenomenon was observed in both groups following 5FU but not cyclophosphamide. Levamisole did not improve the depression of in vitro T cell function produced by cyclophosphamide, but alleviated that following 5FU if administerd after a delay of 3 days. This effect was somewhat marginal but seen consistently in both normal and tumour bearing animals. The combination of glucan with either cytotoxic agent significantly worsened in vitro T cell function, even if the timing of each drug was varied. This observation is interpreted as a directly depressive effect of glucan on T cell function, revealed only in conjunction with cytotoxic therapy. A similar effect was also seen following C parvum but not thiabendazole. The use of a small priming dose of either chemotherapeutic agent did not alleviate the immunosuppressive effect of a subsequently administered large dose. Wide variation of the priming delay for cyclophosphamide did not alter this conclusion. Similarly no benefit was gained either from the regular administration of cimetidine, or the timing of cytotoxic injections to opposing extremes of diurnal rhythms. The difficulties encountered in this field of research and questions for future study are discussed.
Date of award1983-01-01
Author affiliationCollege of Medicine, Biological Sciences and Psychology
Awarding institutionUniversity of Leicester