{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:34:22Z","timestamp":1788953662827,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T00:00:00Z","timestamp":1570492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001167","name":"Cancer Council ACT","doi-asserted-by":"publisher","award":["APP1103848"],"award-info":[{"award-number":["APP1103848"]}],"id":[{"id":"10.13039\/501100001167","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations, <jats:italic>GSTZ1<\/jats:italic> genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3\u00a0months with a loading dose. Pharmacokinetics were performed on day 1 and 8. Trough and peak concentrations of DCA were measured monthly. <jats:italic>GSTZ1<\/jats:italic> genotypes were correlated with drug concentrations, tolerability, and disease outcomes. One patient responded and two patients showed a partial response after one month of DCA treatment, which included the loading dose. The initial half\u2010life of DCA was shorter in two patients, correlating with heterozygosity for <jats:italic>GSTZ1*A<\/jats:italic> genotype, a high enzyme activity variant. Over 3\u00a0months, one patient maintained DCA trough concentrations approximately\u00a0threefold higher than other patients, which correlated with a low activity promoter genotype (\u22121002A, rs7160195) for <jats:italic>GSTZ1<\/jats:italic>. This patient displayed the strongest response, but also the strongest neuropathy. Overall, serum concentrations of DCA were sufficient to inhibit the constitutive target PDK2, but unlikely to inhibit targets induced in cancer. Promoter <jats:italic>GSTZ1<\/jats:italic> polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. Novel dosing regimens may be necessary to achieve effective DCA concentrations in most cancer patients while avoiding neuropathy.<\/jats:p>","DOI":"10.1002\/prp2.526","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T06:50:12Z","timestamp":1570603812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["<i>GSTZ1<\/i> genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial"],"prefix":"10.1002","volume":"7","author":[{"given":"Dan Dan","family":"Tian","sequence":"first","affiliation":[{"name":"ACRF Department of Cancer Biology and Therapeutics The John Curtin School of Medical Research The Australian National University Canberra ACT Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6000-0374","authenticated-orcid":false,"given":"Samuel 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