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Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant
V Appierto1, E Cavadini, R Pergolizzi
1Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, 20133, Italy.
British Journal of Cancer
|June 1, 2001
Summary
Acquired resistance to fenretinide (HPR) in ovarian cancer cells involves reduced drug accumulation and increased metabolism. This resistance is linked to changes in marker expression, suggesting a more differentiated state.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Fenretinide (HPR) is a synthetic retinoid investigated for ovarian cancer treatment.
- Understanding mechanisms of drug resistance is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the development and characteristics of acquired resistance to fenretinide (HPR) in human ovarian carcinoma cells.
Main Methods:
- Exposure of A2780 ovarian cancer cells to increasing concentrations of HPR to induce resistance.
- Assessment of cross-resistance to other retinoids.
- Evaluation of colony-forming ability, retinoic acid receptor beta (RARbeta) expression, cell surface marker expression, reactive oxygen species levels, and drug pharmacokinetics.
Main Results:
- HPR-resistant A2780/HPR cells developed a 10-fold resistance to HPR but not to CD437.
- Colony-forming ability in agar was reduced by 3-fold in resistant cells.
- HPR resistance correlated with increased RARbeta expression, reduced expression of tumor progression markers (HER-2, laminin receptor, beta1 integrin), and altered HPR pharmacokinetics (lower intracellular levels, presence of a metabolite).
Conclusions:
- Acquired resistance to HPR in ovarian cancer cells is associated with changes in marker expression indicative of a more differentiated phenotype.
- Reduced drug accumulation and increased metabolism are likely contributors to HPR resistance.