The longterm objectives of this radiobiological study are centered upon finding combinations of radiation with cytotoxic drugs whose effects are superior to those of the constituent modalities alone or of their algebraic sums. There are 10 specific aims which include: To investigate schedule dependence for combinations of cis-dichlordiammine platinum II (c-DDP) and radiation, examining different fractionated radiation courses; to determine whether the addition of 5-FU to c-DDP and radiation can enhance therapeutic effect as a function of sequence and schedule; to investigate schedule dependence for combinations of cyclophosphamide (CY) with fractionated irradiation; to investigate whether specific electron- affinic sensitizers can further enhance optimal c-DDP and CY radiation combinations; to investigate the effectiveness of radiation combined with multiple drug regimens; to confirm the correlation between breathing rate and pulmonary fibrosis by studying post-treatment fibrogenesis; to investigate the kinetics of cell death in tumor cells by time lapse cinemicrography; to further define the protective effect of Interleukin-1 (IL-1) against whole body radiation lethality; to investigate protective effect of IL-1 against CY lethality; to investigate whether IL-1 affects the sensitivity of normal tissues other than the bone marrow, viz. intestinal mucosa; and to determine whether IL-I can improve the therapeutic effectiveness of chemotherapy/radiotherapy combinations. All experiments will be done in inbred SPF mice either with syngeneic tumors (RIF-I, SCCVII, EMT6, KHT) or on normal tissues. Tumor response will be assessed primarily by regrowth delay; lung response primarily by breathing rate; and intestinal response primarily by crypt survival. This health- related project is directly applicable to human cancer therapy.
