The overall goal of this study is to determine whether the cytokine interleukin-1 (IL-1) can be used to increase the therapeutic efficacy of chemotherapeutic agents. IL-1, a product of the cells of the macrophage/monocyte series, is a multifunctional cytokine that potentiates hematopoiesis, induces the synthesis of CSF in vitro and in vivo, and plays a central role in T and B cell activation. Data from our laboratory demonstrate that treatment of normal mice with IL-1 causes significant neutrophilia, increases serum CSF levels, increases number of granulocyte and macrophage progenitor cells, suppresses erythroid progenitor cells, and hastens myeloid recovery following cyclophosphamide (CP) treatment. We have also found that IL-1 alone causes acute hemorrhagic necrosis of solid tumors in vivo and significantly reduces tumor blood flow, clonogenic cell viability and proliferation. Thus, IL-1 has the potential to substantially increase the therapeutic index of cytotoxic drugs by reducing their dose- limiting myelosuppression, by permitting higher or more frequent administration of chemotherapeutic agents, and by enhancing the anti-timor effects of the drugs. This will be directly and systematically tested in the well-characterized RIF-1 model system through the following specific aims: 1) to establish the optimum effective dose of IL-1, to determine the ability of this dose to increase the maximum tolerated dose of cyclophosphamide in normal and tumor-bearing animals, and to characterize the effect of this therapy on hematopoiesis; 2) to determine whether the combination of IL-1 and high dose cyclophosphamide possesses greater anti-tumor effects than conventional doses of cyclophosphamide alone; 3) to determine whether IL-1 enhances the anti-tumor effects of cytotoxic drug therapy by augmenting immunological reactivity against the tumor, stimulating production of other cytokines or affecting tumor vascular physiology; and, 4) to determine whether the addition of specific cytokines to the combination therapy with Il-1 and cyclophosphamide will improve the hematopoietic and anti- tumor effects. The results of this study could provide the groundwork for use of cytokines in combination with cytotoxic drugs to improve the treatment of human malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA048077-01
Application #
3192029
Study Section
(SRC)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Amc Cancer Research Center
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80214
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Johnson, C S; Chang, M J; Yu, W D et al. (1993) Synergistic enhancement by interleukin-1 alpha of cisplatin-mediated antitumor activity in RIF-1 tumor-bearing C3H/HeJ mice. Cancer Chemother Pharmacol 32:339-46
Chang, M J; Pourbohloul, S C; Yu, W D et al. (1992) Differential effect in vitro of tumor necrosis factor-alpha (TNF) on normal and virus-infected erythroid progenitors from Friend virus (FVA)-infected mice. Exp Hematol 20:1271-7
Braunschweiger, P G; Jones, S A; Johnson, C S et al. (1991) Interleukin-1 alpha-induced tumour pathophysiologies can be exploited with bioreductive alkylating agents. Int J Radiat Biol 60:369-72
Braunschweiger, P G; Jones, S A; Johnson, C S et al. (1991) Potentiation of mitomycin C and porfiromycin antitumor activity in solid tumor models by recombinant human interleukin 1 alpha. Cancer Res 51:5454-60

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