Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Dec;83(12):1599–1606. doi: 10.1054/bjoc.2000.1503

Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours

S L Cheeseman 1, M Brannan 2, A McGown 3, P Khan 3, C Gardner 4, L Gumbrell 4, D Dickens 1, M Ranson 1
PMCID: PMC2363467  PMID: 11104552

Abstract

CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C max and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C max and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V d and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m2 because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m2 daily × 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination. © 2000 Cancer Research Campaign http://www.bjcancer.com

Keywords: CT-2584 HMS, phosphatidic acid, Phase I, pharmacokinetic

Full Text

The Full Text of this article is available as a PDF (79.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bi K., Roth M. G., Ktistakis N. T. Phosphatidic acid formation by phospholipase D is required for transport from the endoplasmic reticulum to the Golgi complex. Curr Biol. 1997 May 1;7(5):301–307. doi: 10.1016/s0960-9822(06)00153-9. [DOI] [PubMed] [Google Scholar]
  2. English D., Cui Y., Siddiqui R. A. Messenger functions of phosphatidic acid. Chem Phys Lipids. 1996 May 24;80(1-2):117–132. doi: 10.1016/0009-3084(96)02549-2. [DOI] [PubMed] [Google Scholar]
  3. Exton J. H. Cell signalling through guanine-nucleotide-binding regulatory proteins (G proteins) and phospholipases. Eur J Biochem. 1997 Jan 15;243(1-2):10–20. doi: 10.1111/j.1432-1033.1997.t01-1-00010.x. [DOI] [PubMed] [Google Scholar]
  4. Khan P., Abbas S., Cheeseman S., Ranson M., McGown A. T. Development and validation of a sensitive solid-phase extraction and high-performance liquid chromatography assay for the novel antitumour agent CT2584 in human plasma. J Chromatogr B Biomed Sci Appl. 1999 Jan 22;721(2):279–284. doi: 10.1016/s0378-4347(98)00491-5. [DOI] [PubMed] [Google Scholar]
  5. Martin A., Gomez-Muñoz A., Waggoner D. W., Stone J. C., Brindley D. N. Decreased activities of phosphatidate phosphohydrolase and phospholipase D in ras and tyrosine kinase (fps) transformed fibroblasts. J Biol Chem. 1993 Nov 15;268(32):23924–23932. [PubMed] [Google Scholar]
  6. Siddiqui R. A., English D. Phosphatidic acid elicits calcium mobilization and actin polymerization through a tyrosine kinase-dependent process in human neutrophils: a mechanism for induction of chemotaxis. Biochim Biophys Acta. 1997 Nov 8;1349(1):81–95. doi: 10.1016/s0005-2760(97)00085-4. [DOI] [PubMed] [Google Scholar]
  7. Siddiqui R. A., Yang Y. C. Interleukin-11 induces phosphatidic acid formation and activates MAP kinase in mouse 3T3-L1 cells. Cell Signal. 1995 Mar;7(3):247–259. doi: 10.1016/0898-6568(94)00083-n. [DOI] [PubMed] [Google Scholar]
  8. Song J. G., Pfeffer L. M., Foster D. A. v-Src increases diacylglycerol levels via a type D phospholipase-mediated hydrolysis of phosphatidylcholine. Mol Cell Biol. 1991 Oct;11(10):4903–4908. doi: 10.1128/mcb.11.10.4903-4908.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Song J., Foster D. A. v-Src activates a unique phospholipase D activity that can be distinguished from the phospholipase D activity activated by phorbol esters. Biochem J. 1993 Sep 15;294(Pt 3):711–717. doi: 10.1042/bj2940711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Waite K. A., Wallin R., Qualliotine-Mann D., McPhail L. C. Phosphatidic acid-mediated phosphorylation of the NADPH oxidase component p47-phox. Evidence that phosphatidic acid may activate a novel protein kinase. J Biol Chem. 1997 Jun 13;272(24):15569–15578. doi: 10.1074/jbc.272.24.15569. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES