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Modulation of tumor hypoxia by conventional chemotherapeutic agents
1Medical Biophysics Dept., B.C. Cancer Research Centre, Vancouver, Canada.
Purpose:
We have evaluated the capacity of a number of common cancer chemotherapeutic drugs to modulate the oxygenation of human tumor xenografts growing in murine hosts.
Methods And Materials:
Considerable effort has been expended on developing methods to radiosensitize hypoxic cells, or to selectively kill them with appropriate chemicals. Another approach, suggested by our ongoing studies with spheroids in vitro, is to modify tumor oxygenation by physiological means. The feasibility of this approach is illustrated in this article using human tumor xenografts in mice treated with doxorubicin or mitomycin C plus radiation. The therapeutic potential of the combination treatments has been assessed using fluorescence-activated cell sorting techniques to isolate and differentially study hypoxic vs. aerobic cell subpopulations from the xenografts. Additionally, drug-induced changes in blood flow have been quantified at the macroscopic level with laser Doppler flowmetry, and at the microregional level with image analysis techniques.
Results:
At doses which produced only modest amounts of tumor cell killing, doxorubicin and mitomycin C markedly altered tumor blood flow in all tumor types examined, and with all assays used.
Conclusion:
Common anti-cancer agents may find new use as blood flow modifiers for combined modality treatments, in addition to their conventional use as "pure" cytotoxins.
Insights
Common chemotherapy drugs like doxorubicin and mitomycin C can alter tumor blood flow, potentially enhancing cancer treatment when combined with radiation therapy.
Area of Science:
- Oncology
- Cancer Therapeutics
- Tumor Microenvironment
Background:
- Hypoxic cells in tumors are resistant to radiation and chemotherapy.
- Developing strategies to overcome tumor hypoxia is crucial for effective cancer treatment.
- Modulating tumor oxygenation through physiological means offers a novel therapeutic approach.
Purpose of the Study:
- To evaluate the ability of common chemotherapy drugs to alter oxygenation in human tumor xenografts.
- To assess the therapeutic potential of combining chemotherapy with radiation therapy.
- To investigate the impact of chemotherapy on tumor blood flow and cell subpopulations.
Main Methods:
- Human tumor xenografts in mice were treated with doxorubicin or mitomycin C plus radiation.
- Fluorescence-activated cell sorting was used to analyze hypoxic and aerobic cell subpopulations.
- Laser Doppler flowmetry and image analysis quantified drug-induced changes in tumor blood flow.
Main Results:
- Doxorubicin and mitomycin C significantly altered tumor blood flow across various tumor types.
- These alterations in blood flow occurred even at drug doses with modest tumor cell killing.
- Chemotherapy effectively modulated the tumor microenvironment's oxygenation status.
Conclusions:
- Common chemotherapy agents can act as effective blood flow modifiers.
- This blood flow modulation offers a new strategy for combined modality cancer treatments.
- Chemotherapeutic drugs may have a dual role: as cytotoxins and as agents to improve treatment efficacy through vascular effects.