title: Dose escalation of N,N',N"-triethylenethiophosphoramide combined with pentoxifylline for advanced breast cancer.
abstract: Pentoxifylline potentiates the cytotoxicity of alkylating agents in preclinical models. In this study we sought to define the maximum tolerated dose (MTD) of N,N',N"-triethylenethiophosphoramide (thioTEPA) with pentoxifylline, and to estimate the antitumor response to this combination in previously treated breast cancer patients. Thirty-five previously treated advanced breast cancer patients received 70 cycles (median, 2 cycles/patient; range, 1-6) of 1600 mg of oral sustained release pentoxifylline every 8 h for 4 doses in combination with escalating doses of i.v. bolus thioTEPA 40-65 mg/m2 administered 3 h after the second dose of pentoxifylline. Thrombocytopenia was dose limiting at 65 mg/m2 of thioTEPA, and the MTD was defined as 60 mg/m2. Among 25 patients treated at the MTD, leukopenia was grade 2 in 9 patients (36%), grade 3 in 4 patients (16%), and grade 4 in 2 patients (8%); thrombocytopenia was grade 2 in 3 patients (12%), grade 3 in 4 patients (16%), and grade 4 in 3 patients (12%). No other thioTEPA-related toxicity was observed. Plasma concentrations of thioTEPA, TEPA, and pentoxifylline were measured in 6 patients. The median (range) area under the plasma concentration versus time curve for thioTEPA was 29.4 microM/h (26. 2-40.5) and for TEPA was 16.3 microM/h (9.2-21.7 microM-h). The median (range) maximal plasma concentration of pentoxifylline and major metabolites I, IV, and V were 1.2 microgram/ml (0.2-7.8), 4.0 microgram/ml (0.5-16.4), 0.4 (range 0.1-0.8), and 2.9 (1.1-5.5), respectively. No objective responses were observed among 21 evaluable patients treated at the MTD (95% confidence interval, 0-15%). The combination of pentoxifylline and thioTEPA is well tolerated but not active in previously treated advanced breast cancer patients. Further clinical trials using commercially available oral sustained release pentoxifylline as a modulator of alkylating agents are not warranted.
authors.affiliation: Breast Evaluation Center, Department of Cell Growth and Regulation, and Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: B J
authors.initials: BJ
authors.lastname: Dezube
authors.forename: O
authors.initials: O
authors.lastname: Tretyakov
authors.forename: J
authors.initials: J
authors.lastname: Wright
authors.forename: B
authors.initials: B
authors.lastname: Cap
authors.forename: I C
authors.initials: IC
authors.lastname: Henderson
authors.forename: D F
authors.initials: DF
authors.lastname: Hayes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016166:Free Radical Scavengers / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010431:Pentoxifylline / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013852:Thiotepa / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016166:Free Radical Scavengers; D013852:Thiotepa; D010431:Pentoxifylline