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SDZ PSC-833--a novel potent in vitro chemosensitizer in multiple myeloma
B Jonsson1, K Nilsson, P Nygren
1Division of Clinical Pharmacology, University Hospital, Uppsala University, Sweden.
Abstract:
Multiple myeloma cell lines and patient tumor samples with and without the expression of the classical multidrug resistance (MDR) phenotype were investigated in vitro for drug induced cytotoxicity and modulation of drug resistance. Overall there was a good correlation in the cell lines between MDR expression, as measured by immunocytochemistry with monoclonal antibodies against P-glycoprotein 170 (Pgp), and in vitro resistance to doxorubicin (dox) and vincristin (vcr). Drug resistance in the cell line RPMI 8226 dox 40, expressing a high level of Pgp, was almost completely reversed by the novel non-immunosuppressive cyclosporin A (CsA) analog SDZ PSC-833 (PSC), while the chemosensitizers verapamil, CsA and quinine, in clinically achievable concentrations, were much less effective. In cell lines with low Pgp expression, PSC and the other chemosensitizers seem equally effective. The patient tumor samples were selected to represent different combinations of Pgp expression, drug resistance and effects of chemosensitizers. PSC and CsA appeared equally potent and resistance modulation was detected not only in Pgp positive, but also in Pgp negative tumor samples. Furthermore, in one case of a Pgp expression myeloma, chemosensitizers were without effect. These findings indicate the need to incorporate in vitro chemosensitivity assays with Pgp determination when the effects of MDR modulating chemosensitizers are to be studied in the clinic.
Insights
SDZ PSC-833 (PSC) effectively reversed multidrug resistance (MDR) in multiple myeloma cell lines by targeting P-glycoprotein (Pgp). This novel agent showed significant potential in overcoming drug resistance, warranting further clinical investigation.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a major challenge in multiple myeloma treatment.
- P-glycoprotein (Pgp) is a key mediator of the MDR phenotype.
- Investigating novel MDR modulators is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To evaluate the efficacy of SDZ PSC-833 (PSC), a novel cyclosporin A analog, in overcoming MDR in multiple myeloma.
- To compare the resistance-modulating effects of PSC with other chemosensitizers like verapamil, CsA, and quinine.
- To assess the correlation between Pgp expression and drug resistance in cell lines and patient tumor samples.
Main Methods:
- In vitro investigation of multiple myeloma cell lines and patient tumor samples.
- Immunocytochemistry using monoclonal antibodies against Pgp to measure MDR expression.
- Drug-induced cytotoxicity assays to assess resistance to doxorubicin and vincristine.
- Evaluation of resistance modulation by PSC, CsA, verapamil, and quinine at clinically achievable concentrations.
Main Results:
- A strong correlation was observed between Pgp expression and in vitro resistance to doxorubicin and vincristine in cell lines.
- PSC demonstrated potent reversal of drug resistance in a Pgp-high expressing cell line (RPMI 8226 dox 40).
- PSC and CsA showed comparable potency in modulating resistance in patient tumor samples, irrespective of Pgp expression status. Some Pgp-expressing tumors were unresponsive to chemosensitizers.
Conclusions:
- SDZ PSC-833 (PSC) is a highly effective MDR modulator in multiple myeloma, particularly in Pgp-expressing cells.
- The study highlights the need for in vitro chemosensitivity assays combined with Pgp determination for clinical studies of MDR modulators.
- Findings suggest that Pgp expression alone may not fully predict response to chemosensitizers in all clinical scenarios.