Local failure remains a major problem for radiotherapy of human solid tumors, and at least a part of tumor radioresistance is generally agreed to be linked to hypoxia. Clinical approaches to overcoming the problem of hypoxic tumor cells have generally been directed toward improving tumor oxygenation and developing better hypoxic cell radiosensitizers. In the laboratory, however, new considerations suggest that tumor hypoxia may present a therapeutic opportunity, and considerable effort is now directed toward developing agents with specific toxicity to hypoxic cells. While intriguing, the practicality of either reducing or exploiting tumor hypoxia nonetheless remains questionable for human disease, largely due to uncertainty regarding the nature of hypoxia in human tumors, and lack of availability of appropriate modifying agents suitable for clinical use. Our ongoing studies with spheroids in vitro, recently extended to human xenografts in vivo, have revealed that a number of agents capable of modifying tumor hypoxia are already in clinical use: common cancer chemotherapeutic drugs. Our intent in this project is to test selected drugs as radiation modifiers in human tumor xenografts in mice, by identifying time and dose schedules which produce radiosensitization, altered blood flow, metabolic perturbations leading to reoxygenation, and/or preferential cytotoxicity. The therapeutic potential of the combination treatments will be assessed using fluorescence-activated cell sorting techniques to isolate and differentially study hypoxic versus aerobic cell subpopulations from the xenografts. Concurrently, drug induced changes in blood flow will be quantified at the macroscopic level with laser Doppler flowmetry, and at the microregional level with image analysis techniques. Oxygen utilization rates will be measured for cells in situ using an innovative fluorescent staining procedure. Using conventional cancer chemotherapy drugs for the specific purpose of modifying the amount and degree of tumor hypoxia is, to the applicant's knowledge, unique to this laboratory. We consequently anticipate that our integrated results will, at the very least, provide novel information concerning the nature and role of hypoxia in the in vivo action and interaction of cisplatin, doxorubicin, mitomycin-C and CCNU with radiation; at best, new treatment schemes entirely feasible for immediate clinical testing will be suggested.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA056600-01
Application #
3200950
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1992-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
British Columbia Cancer Agency
Department
Type
DUNS #
209137736
City
Vancouver
State
BC
Country
Canada
Zip Code
V5 1-L3
Durand, R E; LePard, N E (2000) Effects of mitomycin C on the oxygenation and radiosensitivity of murine and human tumours in mice. Radiother Oncol 56:245-52
Sham, E; Durand, R E (1999) Repopulation characteristics and cell kinetic parameters resulting from multi-fraction irradiation of xenograft tumors in SCID mice. Int J Radiat Oncol Biol Phys 43:617-22
Sham, E; Durand, R E (1999) Cell kinetics and repopulation parameters of irradiated xenograft tumours in SCID mice: comparison of two dose-fractionation regimens. Eur J Cancer 35:850-8
Durand, R E; Raleigh, J A (1998) Identification of nonproliferating but viable hypoxic tumor cells in vivo. Cancer Res 58:3547-50
Durand, R E; Sham, E (1998) The lifetime of hypoxic human tumor cells. Int J Radiat Oncol Biol Phys 42:711-5
Huang, P; Olive, P L; Durand, R E (1998) Use of the comet assay for assessment of drug resistance and its modulation in vivo. Br J Cancer 77:412-6
Durand, R E; LePard, N E (1997) Tumour blood flow influences combined radiation and doxorubicin treatments. Radiother Oncol 42:171-9
Durand, R E; Olive, P L (1997) Physiologic and cytotoxic effects of tirapazamine in tumor-bearing mice. Radiat Oncol Investig 5:213-9
Durand, R E (1997) Tumor repopulation during radiotheraphy: quantitation in two xenografted human tumors. Int J Radiat Oncol Biol Phys 39:803-8
Durand, R E; LePard, N E (1995) Contribution of transient blood flow to tumour hypoxia in mice. Acta Oncol 34:317-23

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