Most human malignancies will respond to current chemotherapeutic treatment regimens, yet few neoplasms can be cured by chemotherapy alone. Development of more effective drugs is thus necessary, but we believe that a high priority should also be placed on optimizing the use of available agents, which in turn requires a better understanding of the factors which modulate drug activity in a tumor. While drug 'resistance' is generally implicated as the cause of treatment failure, it is seldom possible to know when, where, or why resistant cells appear in the tumor mass. This information can, however, be determined in certain laboratory models, like V79 multicell spheroids in tissue culture. We thus intend to evaluate several clinically-used chemotherapeutic agents in spheroids, emphasizing regional and temporal variations in cytotoxicity; our results will suggest ways to use each agent more effectively, and provide additional criteria for selecting (and using) drug combinations. Regional variations in drug efficacy will be studied in spheroids stained with slowly-penetrating, non-toxic fluorescent dyes. Since the dyes are retained in disaggregated cells, a fluorescence- activated cell sorter can be used to select subpopulations with specified stain intensities; the clonogenicity of these sorted cells then defines the drug toxicity throughout the spheroid. The location, timing and degree of resistance to each drug will suggest useful combinations, as well as indicating ways to improve single- agent efficacy. In subsequent multidrug studies, therapeutically useful interactions, including differential (complementary) toxicity, reoxygenation, cell cycle perturbations, metabolic alterations, and/or direct interaction of lesions, will be identified and quantified. The resulting information will supplement that already available for these clinically effective drugs, so promising combinations, doses and sequences and can be evaluated in patients without delay.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA037775-04A1
Application #
3175581
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1984-07-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
4
Fiscal Year
1988
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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