SPECIAL DEPARTMENTS
Authors: Stanley Zucker, S. Gail Eckhardt, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.8.1805 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10764446 Stanley ZuckerxStanley ZuckerSearch for articles by this author S. Gail EckhardtxS. Gail EckhardtSearch for articles by this author , Eric K. RowinskyxEric K. RowinskySearch for articles by this author Show More Veterans Administration Medical Center NorthportNY State University of New York at Stony Brook Stony Brook, NYUniversity of Colorodo Cancer Center DenverCOInstitute for Drug Development Cancer Therapy and Research Center San AntonioTX https://doi.org/10.1200/JCO.2000.18.8.1805 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01042000In Reply:Dr Zucker raises several important issues regarding the optimal use of biologic assays during clinical trials of matrix metalloproteinase (MMP) inhibitors. To date, the incorporation of such assays into clinical trials has been inconsistent and poorly documented. These efforts have also been disorganized, with minimal attempts to validate the assays before clinical development. Although we agree with most of the points made by Zucker, several issues must be clarified. With regard to the terminology used for TIMP-2, we apologize for the error in the abstract that refers to TIMP-2 being the tissue inhibitor of MMP-2. We understand the complexity of TIMP-2 in regulating the activity of MMPs other than MMP-2; however, the literature does support the important role of TIMP-2 in complexing with MMP-2.1,2 In retrospect, although it would have been perhaps more revealing to examine TIMP-1 in the plasma of patients on this trial, the commercial kit for this assay had not been fully developed and validated at the time of the clinical trial. The measurement of active MMP-9 in the study reflected both circulating active MMP-9 and pro-MMP-9 and was based upon similar studies using zymography in clinical trials of marimastat 3. Since the predominant effect of BAY 12-9566 is on the function, and not on the synthesis, of MMPs, we thought it would be worthwhile to determine whether the proportion of potentially functional, circulating MMP-9 decreased over time. In response to the comment about fluctuating plasma concentrations of MMP-9 in cancer patients, we agree that the measurement of plasma MMP-9 is problematic; however, our decision to measure circulating MMP-9 was based upon the prevailing literature and the availability of a well-validated and feasible assay at the time of clinical development. In fact, numerous reports, including those of Zucker et al, have reported elevated plasma concentrations of MMP-2 and/or MMP-9 in patients with cancer.4-6 Although we agree that it may be imprecise to assume that circulating MMP concentrations reflect contributions from diverse tissue sources, further investigations in this area are clearly necessary. While Zucker suggests using alternate, more direct assays, he also notes that such assays “remain to be developed.”Finally, the need to develop appropriate clinical trial designs for these types of agents is well recognized by the clinical oncology community. We believe that is imperative that investigators involved in basic research in MMPs, tumor angiogenesis, and signal transduction, as well as the pharmaceutical industry sponsors of specific therapeutics in clinical trials, devote a significant portion of their preclinical efforts to investigating the use of biologic markers and to developing and validating practical assays that truly reflect the actions of these therapeutics at the tumor target before clinical development. Although it is clear that such strategies will result in the most expedient and fruitful clinical research efforts, there is a paucity of such investigations relative to the large number of such compounds entering clinical trials. The lack of organized efforts toward the development and validation of biologic assays and markers that can readily be used in the clinic, beginning before clinical development, will undoubtedly lead to wasted clinical resources, wasted time, and further delays in the evaluation of many novel classes of targeted therapeutics.11. Howard EK, Bullen EC, Banda MJ: Regulation of the autoactivation of human 72-kDa progelatinase by tissue inhibitor of metalloproteinases-2. J Biol Chem 266::13064,1991-13069, Medline, Google Scholar11. Strongin AY, Marmer BL, Grant GA, et al: Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2. J Biol Chem 268::14033,1993-14039, Medline, Google Scholar11. Wojtowicz-Praga S, Torri J, Johnson M, et al: Phase I trial of marimastat, a novel matrix metalloprotease inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 16::2150,1998-2156, Link, Google Scholar11. Zucker S, Lysik RM, Zarrabi MH, et al: M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res 53::140,1993-146, Medline, Google Scholar11. Iizasa T, Fujisawa T, Suzuki M, et al: Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. Clin Cancer Res 5::149,1999-153, Medline, Google Scholar11. Endo K, Maehara Y, Baba H, et al: Elevated levels of serum and plasma metalloproteinases in patients with gastric cancer. Anticancer Res 17::2253,1997-2258, Medline, Google Scholar