Phase I/II clinical trial of 2‐difluoromethyl‐ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma^*

Q2 · AGRICULTURAL & FORESTRY SCIENCE

Article

Author: Carlos O. Rodriguez ; Teri Guerrero ; Thomas G. O'Brien ; Mark R. Burns ; Katherine A. Skorupski

Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumour regression in mouse models of squamous cell carcinoma (SCC). The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase (ODC) inhibitor, DFMO, and to determine whether this therapy results in reduction in tumour polyamine levels. Thirteen cats with oral SCC received both drugs orally and serial tumour biopsies were obtained for polyamine measurement. Cats were monitored for response to therapy and toxicity. A maximum tolerated dose (MTD) of MQT 1426 when combined with DFMO was determined. Dose‐limiting toxicity was vestibular in nature, but was fully reversible. Spermidine and total polyamine levels decreased significantly in tissues, two cats experienced objective tumour regression and six cats had stable disease. These results suggest that further study of polyamine depletion therapies is warranted.

01 May 2006·International Journal of CancerQ1 · MEDICINE

Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Q1 · MEDICINE

Article

Author: Mark R. Burns ; Andres Klein-Szanto ; David W. Boorman ; Reitha S. Weeks ; Yan Chen ; Thomas G. O'Brien

AbstractUsing a recently developed autochthonous mouse model of squamous cell carcinoma (SCC), a combination therapy targeting polyamine metabolism was evaluated. The therapy combined 2‐difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and MQT 1426, a polyamine transport inhibitor. In 1 trial lasting 4 weeks, combination therapy with 0.5% DFMO (orally, in the drinking water) and MQT 1426 (50 mg/kg i.p., bid) was significantly more effective than with either single agent alone when complete tumor response was the endpoint. In the combination group, 72% of SCCs responded completely vs. 21 and 0% for DFMO and MQT 1426, respectively. A second trial involved a 4‐week treatment period followed by 6 weeks off‐treatment. With apparent cures as an endpoint, combination therapy was again more effective than either agent alone: a 50% apparent cure rate was observed in the combination group vs. 7.7% in the DFMO group. MQT 1426 had no inhibitory effect on SCC ODC activity nor did it enhance the inhibition by DFMO, but SCC polyamine levels declined more rapidly when treated with combination therapy vs. DFMO alone. The apoptotic index in SCCs was transiently increased by combination therapy but not by DFMO alone. Thus, targeting both polyamine biosynthesis and polyamine transport from the tumor microenvironment enhances the efficacy of polyamine‐based therapy in this mouse model of SCC. © 2005 Wiley‐Liss, Inc.

100 Deals associated with MQT-1426

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	MediQuest Therapeutics, Inc.	-

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