We will evaluate the hypothesis that greater antitumor effects can be achieved by appropriately sequencing selected drugs with radiation treatments. The V79 multicell spheroid tumor model is our choice for these studies, since it presents many of the same """"""""drug delivery"""""""" problems of solid tumors, spontaneously develops both non-cycling and hypoxic cell populations, yet grows in an environment that can be precisely controlled and reproduced. We will define effective drugs as those capable of diffusing into the spheroid, and inactivating cells in that tumor-like environment. This will be determined by our recently-developed techniques of fluorescence-activated cell sorting to selectively recover cells from any desired depth of the spheroids; the sorted cells can be assayed for clonogenicity to determine the activity of the drugs, and whether they interact with radiation. We will further determine whether such interaction(s) are cell cycle or oxygen related, and attempt to exploit them in multifraction exposures. We also intend to evaluate whether flow cytometry techniques for monitoring several indicators of cell function following treatment (eg, cell cycle redistribution, mitochondrial function, DNA synthesis rate, or thiol content) can suggest optimum timing for subsequent treatment in multifraction regimens, and perhaps predict the eventual outcome. We anticipate that our results will identify relevant therapeutic regimens, provide insight into basic mechanisms of drug-radiation interactions, and potentially lead to prognostic tests which may prove valuable during human tumor therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037775-02
Application #
3175584
Study Section
Radiation Study Section (RAD)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
British Columbia Cancer Agency
Department
Type
DUNS #
209137736
City
Vancouver
State
BC
Country
Canada
Zip Code
V5 1L3
Brown, R C; Durand, R E (1994) Repair, redistribution and repopulation in V79 spheroids during multifraction irradiation. Cell Prolif 27:343-54
Durand, R E; Olive, P L (1992) Evaluation of bioreductive drugs in multicell spheroids. Int J Radiat Oncol Biol Phys 22:689-92
Durand, R E (1991) Keynote address: the influence of microenvironmental factors on the activity of radiation and drugs. Int J Radiat Oncol Biol Phys 20:253-8
Wilkinson, M F; Fong, A M; Huynh, H et al. (1991) A model system for T-lymphocyte differentiation: regulation of CD4 and CD8 gene expression in SL12.4 T-lymphoma cell clones. Mol Immunol 28:57-68
Durand, R E (1990) Multicell spheroids as a model for cell kinetic studies. Cell Tissue Kinet 23:141-59
Durand, R E (1990) Slow penetration of anthracyclines into spheroids and tumors: a therapeutic advantage? Cancer Chemother Pharmacol 26:198-204
Durand, R E (1990) Cisplatin and CCNU synergism in spheroid cell subpopulations. Br J Cancer 62:947-53
Durand, R E; Chaplin, D J; Olive, P L (1990) Cell sorting with Hoechst or carbocyanine dyes as perfusion probes in spheroids and tumors. Methods Cell Biol 33:509-18
Fengler, J J; Durand, R E (1990) Respiration-induced oxygen gradients in cultured mammalian cells. Int J Radiat Biol 58:133-44
Durand, R E; Vanderbyl, S L (1990) Schedule dependence for cisplatin and etoposide multifraction treatments of spheroids. J Natl Cancer Inst 82:1841-5

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