ORAL ESCALATING DOSE OF CYCLOSPORINE-A COMBINED WITH 4-EPIDOXORUBICININ ADVANCED COLORECTAL-CANCER - A PHASE-I STUDY

Multidrug resistance, a major factor in the resistance to drugs, can b e reversed by cyclosporin A. It is generally given by intravenous rout e. The aim of the present study was to assess the possibility of achie ving useful plasma levels, giving cyclosporin A orally in advanced col orectal cancer patients treated with 4-epidoxorubicin. Cyclosporin A w as given orally twice a day, for four days. The starting study dose wa s 5 mg/kg. Dose in cohorts of 3 patients was escalated to 10, 15, 20, 30, 40 mg/kg if the previous dose was not able to determine the target blood level (2,000 ng/ml). Cyclosporin A blood levels were analyzed b y a specific fluorescence polarization immunoassay method (TDx; Abbot Laboratoires, North Chigaco, IL). 4-epidoxorubicin was given at a fixe d dose of 75 mg/m(2), every 3 weeks. None of the dose levels of cyclos porin A given orally produced the target blood level. Only two patient s, receiving cyclosporin at a dose of 30 mg/kg, and two after a CsA do se of 40 mg/kg, presented blood levels higher than 1,000 ng/ml, but ho wever, lower than 1,500 ng/ml. In conclusion, the oral route of admini stration of cyclosporin does not seem recommendable in order to revers e multidrug resistance because it is not able to produce sufficient pl asma levels.