Interleukin-1 (IL-1), a multifunctional cytokine, induces the synthesis of regulatory molecules which effect endothelial cells, macrophages, T cells and other accessory cells. The applicant has demonstrated previously that IL-la induces acute tumor hemorrhagic necrosis, changes in tumor blood flow and increases clonogenic tumor cell kill. Under support of this grant, they have demonstrated that IL-la significantly enhances cisplatin (cDDP) and carboplatin (CBDCA) anti- tumor activities with time-dependent differences. To minimize toxicity, IL-la was administered by low dose continuous infusion and shown to maintain enhanced CBDCA anti-tumor effects and diminished CBDCA- induced thrombocytopenia. Using a method developed in the applicant's laboratory for the isolation of freshly derived tumor endothelial cells, they have demonstrated that IL-la/ interferon-g (IFN-g) (acytokine induced in the tumor after IL-la) induces a significant level of NO as compared to normal endothelial cells. Tumor-endothelial cells also express increased levels of message for entactin, an extracellular matrix protein. Lastly, IL-la significantly enhanced anti-tumor efficacy of cyclophosphamide (CTX) alone, CTX/CBDCA or CBDCA/etoposide (VP-16).
The aims of this study are: 1) to characterize endothelial cells isolated from untreated and IL-la treated tumor-bearing mice with normal endothelial cells with respect to proliferative response, cellular adhesion molecule (CAM) expression, the ability to synthesize matrix metalloproteinases; 2) to determine whether NO production by tumor-derived endothelial cells contributes to IL-1a induced anti-tumor effects and potentiation of platinum-mediated anti-tumor activities; 3) to determine whether a relationship exists between gene expression of entactin, an extracellular matrix protein, and IL-1a induced effects on tumor endothelium in vitro and in vivo and 4) to examine the ability of IL-la to enhance the therapeutic efficacy of CBDCA in combination with VP-16. These studies will provide the groundwork for the use of IL-1 or related cytokines either alone or in combination with cytotoxic drugs for the therapy of solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA048077-12
Application #
2871736
Study Section
Special Emphasis Panel (ZRG2-ET-1 (01))
Program Officer
Hecht, Toby T
Project Start
1989-09-01
Project End
2000-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yu, W D; Chang, M J; Trump, D L et al. (1997) Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity. Cancer Immunol Immunother 44:316-22
McElwain, M C; Modzelewski, R A; Yu, W D et al. (1997) Vitamin D: an antiproliferative agent with potential for therapy of squamous cell carcinoma. Am J Otolaryngol 18:293-8
Chang, M J; Modzelewski, R A; Russell, D M et al. (1996) Interleukin 1 alpha and gamma-interferon induction of nitric oxide production from murine tumor-derived endothelial cells. Cancer Res 56:886-91
Grandis, J R; Chang, M J; Yu, W D et al. (1995) Antitumor activity of interleukin-1 alpha and cisplatin in a murine model system. Arch Otolaryngol Head Neck Surg 121:197-200
Chang, M J; Yu, W D; Reyno, L M et al. (1994) Potentiation by interleukin 1 alpha of cisplatin and carboplatin antitumor activity: schedule-dependent and pharmacokinetic effects in the RIF-1 tumor model. Cancer Res 54:5380-6
Modzelewski, R A; Davies, P; Watkins, S C et al. (1994) Isolation and identification of fresh tumor-derived endothelial cells from a murine RIF-1 fibrosarcoma. Cancer Res 54:336-9
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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