title: Pilot study of multiple chemotherapy resistance modulators plus epirubicin in the treatment of resistant malignancies.
abstract: We studied the toxicity and efficacy of adding to epirubicin five resistance modulators in the treatment of resistant solid tumors. Additional drugs were added in successive cohorts of patients, such that cohort 1 patients received two drugs along with their epirubicin, while cohort 4 patients received five modulators along with their epirubicin. Metronidazole, tamoxifen (cohort 1), dipyridamole (cohort 2), ketoconazole (cohort 3) and cyclosporin (cohort 4) were administered with epirubicin. A total of 22 patients were treated. Nausea and vomiting was usually mild to moderate. There was an unexpectedly high incidence of possible cardiac toxicity associated with treatment, although in some patients it was uncertain whether or not observed cardiac events were related to treatment. Granulocytopenia was significant in all four cohorts, but it was unclear whether it was increased by the modulators. There were two febrile neutropenic events in cohorts 1 and 2 successfully treated with antibiotics, and three septic deaths (one in each of cohorts 1, 2 and 4). It was elected to discontinue enrollment on the study prematurely in light of cardiac and other toxicity seen in the first two patients accrued in cohort 4. A single response was observed. While this approach is feasible, the observed toxicity and the difficulty patients experienced in ingesting the large number of prescribed pills will make further exploration of this approach difficult.
authors.affiliation: The Ontario Cancer Treatment and Research Foundation, Ottawa Regional Cancer Centre, Canada.
authors.forename: D J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: M C
authors.initials: MC
authors.lastname: Cripps
authors.forename: R
authors.initials: R
authors.lastname: Goel
authors.forename: S
authors.initials: S
authors.lastname: Dahrouge
authors.forename: J
authors.initials: J
authors.lastname: Yau
authors.forename: E
authors.initials: E
authors.lastname: Tomiak
authors.forename: S
authors.initials: S
authors.lastname: Huan
authors.forename: K
authors.initials: K
authors.lastname: Soltys
authors.forename: A
authors.initials: A
authors.lastname: Prosser
authors.forename: R A
authors.initials: RA
authors.lastname: Davies
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage* / Q000009:adverse effects; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000994:Antitrichomonal Agents / Q000008:administration & dosage / Q000009:adverse effects; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects; D004176:Dipyridamole / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010865:Pilot Projects; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000277:Adjuvants, Pharmaceutic; D000903:Antibiotics, Antineoplastic; D000935:Antifungal Agents; D018931:Antineoplastic Agents, Hormonal; D000994:Antitrichomonal Agents; D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D013629:Tamoxifen; D008795:Metronidazole; D015251:Epirubicin; D004176:Dipyridamole; D016572:Cyclosporine; D007654:Ketoconazole