This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tetef, M. L. Articles by Doroshow, J. H. Search for Related Content PubMed PubMed Citation Articles by Tetef, M. L. Articles by Doroshow, J. H.

Phase I Trial of 96-Hour Continuous Infusion of Dexrazoxane in Patients with Advanced Malignancies¹

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California 91010 [M. L. T., T. W. S., W. C., L. L., K. M., R. M., J. R., S. S., G. S., Y. Y., J. H. D.]; Division of Medical Oncology, University of Southern California-Norris Comprehensive Cancer Center, Los Angeles, California 90033 [S. G., K. J, H-J. L.]; and Division of Medical Oncology, University of California, Davis Medical Center, Sacramento, California 95817 [D. G.]

Dexrazoxane is a bidentate chelator of divalent cations. Pretreatment with short infusions of dexrazoxane prior to bolus doxorubicin has been shown to lessen the incidence and severity of anthracycline-associated cardiac toxicity. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular retention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-h infusion of dexrazoxane was performed. Dexrazoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocyte-colony stimulating factor at a dose of 5 µg/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and analyzed for dexrazoxane by high-performance liquid chromatography. Urine collections were performed at baseline and during the infusion to determine the renal clearance of dexrazoxane and the excretion rate of divalent cations. Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m²/day. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 patients treated at 250 mg/m²/day, grade 3 thrombocytopenia and grade 4 nausea and vomiting in 1 patient treated at 221 mg/m²/day, grade 4 diarrhea and grade 3 nausea and vomiting in 1 patient treated at 221 mg/m²/day, and grade 3 hypertension in 1 patient treated at 166.25 mg/m²/day. Steady-state dexrazoxane levels ranged from 496 µg/l (2.2 µM) to 1639 µg/l (7.4 µM). Dexrazoxane plasma CL_ss and elimination t_1/2 were 7.2 ± 1.6 l/h/m² and 2.0 ± 0.8 h, respectively. The mean percentage of administered dexrazoxane recovered in the urine at steady state was 30% (range, 10–66%). Urinary iron and zinc excretion during the dexrazoxane infusion increased in 12 of 18 and 19 of 19 patients by a median of 3.7- and 2.4-fold, respectively. These results suggest that dexrazoxane as a 96-h infusion can be safely administered with granulocyte-colony stimulating factor at doses that achieve plasma levels that have been demonstrated previously to inhibit topoisomerase II activity and to induce apoptosis in vitro. Additional studies will be required to determine whether the combination of continuous infusions of dexrazoxane and doxorubicin would provide enhanced cardioprotection compared with the currently recommended bolus or short infusion schedules.

This article has been cited by other articles:

				S. E. Lipshultz, N. Rifai, V. M. Dalton, D. E. Levy, L. B. Silverman, S. R. Lipsitz, S. D. Colan, B. L. Asselin, R. D. Barr, L. A. Clavell, et al. The Effect of Dexrazoxane on Myocardial Injury in Doxorubicin-Treated Children with Acute Lymphoblastic Leukemia N. Engl. J. Med., July 8, 2004; 351(2): 145 - 153. [Abstract] [Full Text] [PDF]

				G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]

				B. T. Greene, J. Thorburn, M. C. Willingham, A. Thorburn, R. P. Planalp, M. W. Brechbiel, J. Jennings-Gee, J. Wilkinson IV, F. M. Torti, and S. V. Torti Activation of Caspase Pathways during Iron Chelator-mediated Apoptosis J. Biol. Chem., July 5, 2002; 277(28): 25568 - 25575. [Abstract] [Full Text] [PDF]