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Site-dependent differences in response of the UV-2237 murine fibrosarcoma to systemic therapy with adriamycin
A N Staroselsky1, D Fan, C A O'Brian
1Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Abstract:
Murine fibrosarcoma UV-2237MM cells were implanted into different organs of syngeneic C3H/HeN mice. The resultant tumors were treated by i.v. administration of Adriamycin (ADR). Despite the high sensitivity of the fibrosarcoma cells to ADR in vitro, the established tumors growing in vivo exhibited marked differences in their responses to ADR. Tumors growing in the subcutis and the spleen were ADR-sensitive, whereas lung metastases were not. The resistance of lung metastases to ADR was not due to selection of a drug-resistant population since tumor cells isolated from lung metastases were highly sensitive to ADR under in vitro conditions. The responsiveness of skin and spleen tumors to ADR was due neither to increased blood supply nor to preferential accumulation of ADR, since both parameters were higher in lung metastases. Protein kinase C activity levels correlated with ADR resistance in the closely related murine fibrosarcoma cell line UV-2237 and its ADR-selected multidrug-resistant variants. However, nearly identical levels of protein kinase C activity were found in UV-2237MM tumors growing in the lung, spleen, and subcutis, indicating that protein kinase C activity levels did not account for the different responses to ADR. The present studies suggest that the organ environment influences the response of UV-2237MM to ADR administered systemically. This finding may have implications for the design of animal models for therapy of disseminated cancer.
Insights
The organ environment significantly impacts cancer treatment outcomes. Lung metastases showed resistance to Adriamycin (ADR), unlike tumors in skin and spleen, suggesting environmental factors influence drug efficacy in vivo.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Murine fibrosarcoma UV-2237MM cells exhibit high sensitivity to Adriamycin (ADR) in vitro.
- Established tumors in vivo show varied responses to ADR depending on their location.
- Lung metastases display resistance to ADR, contrasting with sensitive tumors in the subcutis and spleen.
Purpose of the Study:
- To investigate the differential response of murine fibrosarcoma UV-2237MM tumors to Adriamycin (ADR) based on organ microenvironment.
- To determine the mechanisms underlying ADR resistance in lung metastases.
- To assess the influence of the organ environment on systemic cancer therapy.
Main Methods:
- Implantation of murine fibrosarcoma UV-2237MM cells into different organs of syngeneic C3H/HeN mice.
- Intravenous administration of Adriamycin (ADR) to treat established tumors.
- In vitro sensitivity assays of tumor cells isolated from various organs.
- Measurement of blood supply and ADR accumulation in tumors.
- Analysis of Protein Kinase C activity levels.
Main Results:
- Tumors in the subcutis and spleen were sensitive to ADR, while lung metastases were resistant.
- Resistance in lung metastases was not due to drug-resistant cell selection.
- Increased blood supply and ADR accumulation were higher in lung metastases, not explaining resistance.
- Protein Kinase C activity levels were similar across all tumor locations and did not correlate with ADR response.
Conclusions:
- The organ microenvironment plays a critical role in modulating the response of UV-2237MM tumors to systemically administered Adriamycin.
- Findings suggest that the tumor's location influences drug efficacy, independent of intrinsic cellular sensitivity or drug distribution.
- This highlights the importance of considering the organ environment in the design of preclinical cancer models and therapeutic strategies for disseminated disease.