[SDZ PSC 833: a novel modulator of MDR].
SDZ PSC 833 is a novel compound able to reverse the resistance to chemotherapy of cancer cells with the multidrug resistance (MDR) phenotype by inhibiting the 170 kd P-glyco-protein (P-gp). In vitro studies show that SDZ PSC 833 directly interacts with, but is not transported by P-gp, although the exact mechanism of action has not yet been defined. In cells with the MDR phenotype, intracellular concentration of various P-gp-transported anticancer drugs is restored to the same level as in sensitive cells by SDZ PSC 833 concentrations of 0.8 microM to 3.0 microM. In vivo SDZ PSC 833 was highly active in potentiating the anti-tumour activity of all tested anticancer drugs (ACs) in both sensitive and MDR tumours. Sensitivity of non-MDR tumours was increased by SDZ PSC 833 through pharmacokinetic interactions, that result in enhanced area-under-the-curve (AUC) of P-gp-transported ACs. However, an increased AC bioavailability is not sufficient to explain the therapeutic benefit of SDZ PSC 833 co-treatment in MDR tumour-bearing mice: in these animals, no survival increase could be achieved with the AC alone by simply increasing the cytotoxin dosage up to doses that were severely toxic for the non-tumour-bearing mice. In a series of phase I/II studies, the recommended doses of SDZ PSC 833 were established at: 10 mg/kg/day i.v. as a 24-hour continuous infusion after a 2 mg/kg loading dose as a 2-hour infusion; 20 mg/kg orally divided four times daily in solid tumours or 16 mg/kg orally divided four times daily in multiple myeloma. The dose limiting toxicity of SDZ PSC 833 is ataxia, which appears to be reversible and dose-related. Moreover, a predictable change in pharmacokinetic parameters of concomitantly administered P-gp-transported AC(s) which usually necessitate a 30-60% reduction from the standard dose of the AC in order to maintain the same time-exposure and dose-related toxicity of the cytotoxic drug alone. The results of experiments both in vitro and in vivo suggested that adequate blood levels (i.e. > or = 1.0 microM) of SDZ PSC 833 must be reached before and maintained during the administration of concomitant AC(s), in order to maximally reverse MDR. At the recommended doses, blood concentrations exceeding 1000 ng/mL (1.0 microM) can be achieved after both i.v. and oral administration. Indeed, SDZ PSC 833 concentrations that fully reverse MDR in vitro are achievable in vivo, plasma samples from patients treated with SDZ PSC 833 restored the sensitivity of MDR human sarcoma cells to paclitaxel, etoposide and doxorubicin. Clinical studies completed so far aimed first to determine the dose of both SDZ PSC 833 and the concomitant AC(s) to be used in ongoing pivotal trials. These studies accrued advanced stage cancer patients, however, tumour responses have been observed in both solid and hematological tumours. The in vitro finding that treatment with SDZ PSC 833 may suppress the activation of the MDR1 gene and prevent the emergence of resistant cancer cell clones with the MDR phenotype might support the use of this MDR modulator in earlier stages of disease.
Covelli
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Clinical Research & Development, Novartis, Basel, Switzerland.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D003524:Cyclosporins / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019450:Genes, MDR; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype
D000970:Antineoplastic Agents; D003524:Cyclosporins; C070272:valspodar