Publications [#168966] of Mark W. Dewhirst

Papers Published

1. ML Hauck, SM LaRue, WP Petros, JM Poulson, D Yu, I Spasojevic, AF Pruitt, A Klein, B Case, DE Thrall, D Needham, MW Dewhirst, Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors., Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 12 no. 13 (July, 2006), pp. 4004-10, ISSN 1078-0432 [doi]
   (last updated on 2013/05/16)

   Abstract:
   OBJECTIVE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. METHODS: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSIONS: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.

   Keywords:
   Animals • Antineoplastic Agents • Carcinoma • Combined Modality Therapy • Dog Diseases • Dogs • Dose-Response Relationship, Drug • Doxorubicin • Drug Administration Schedule • Drug Delivery Systems • Female • Hyperthermia, Induced • Liposomes • Male • Maximum Tolerated Dose • Microwaves • Sarcoma • Temperature • Treatment Outcome • administration & dosage* • adverse effects • methods* • pharmacokinetics • therapeutic use • therapy • therapy* • veterinary*