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Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening
E Boven1, H M Pinedo, A H van Hattum
1Department of Medical Oncology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Abstract:
We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.
Insights
This study evaluated ten human soft-tissue sarcoma (STS) xenografts against five chemotherapy agents. Chemosensitivity in these models correlated with clinical outcomes in adult STS patients, suggesting their utility in predicting treatment response.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Soft-tissue sarcoma (STS) is a rare cancer with limited treatment options.
- Predicting patient response to chemotherapy is crucial for effective treatment strategies.
- Developing reliable preclinical models for STS is essential for drug discovery and testing.
Purpose of the Study:
- To establish and characterize transplantable human soft-tissue sarcoma (STS) xenografts.
- To assess the chemosensitivity of these STS xenografts to standard anti-cancer agents.
- To explore potential molecular mechanisms underlying drug resistance in STS.
Main Methods:
- Ten human STS xenografts were established in nude mice.
- Xenografts were treated with maximum tolerated doses of doxorubicin, cyclophosphamide, ifosfamide, vincristine, and etoposide.
- Tumor growth inhibition was measured, and molecular markers (MDR1 mRNA, topoisomerase IIalpha mRNA, glutathione levels, and glutathione S-transferase activity) were analyzed.
Main Results:
- Significant growth inhibition (>75%) was observed for doxorubicin (20%), cyclophosphamide (30%), ifosfamide (20%), and vincristine (20%). Etoposide showed no efficacy.
- MDR1 mRNA and topoisomerase IIalpha mRNA levels did not correlate with resistance to tested drugs.
- Glutathione-related enzyme activities were not associated with resistance, though glutathione S-transferase pi was predominant.
Conclusions:
- STS xenografts demonstrate chemosensitivity patterns that correlate with clinical response rates in adult STS patients.
- Low topoisomerase IIalpha mRNA levels may contribute to intrinsic resistance to agents like doxorubicin.
- Additional factors likely influence the moderate response observed with alkylating agents in STS.