Alan Hastings Drummond

Preclinical and clinical studies of MMP inhibitors in cancer.

ABSTRACT: The role of matrix metalloproteinases in tumor angiogenesis and growth is now well recognized for models of both human and animal cancer. Clinical studies currently under way with the prototype matrix metalloproteinase inhibitor, marimastat, will establish whether inhibitors of these enzymes are of benefit in the treatment of different types of human cancer. On chronic therapy in humans, marimastat induces a reversible tendinitis that can also be detected in certain animal species. This paper compares the ability of broad‐spectrum and various types of selective matrix metalloproteinase inhibitors to induce tendinitis and to exhibit anticancer effects in an animal cancer model. Under conditions in which both systemic exposure and inhibitor potency are controlled, selective inhibitors are less pro‐tendinitic, but are weaker anticancer agents than broad‐spectrum agents such as marimastat. The clinical relevance of these findings is discussed.

Lithium and inositol lipid-linked signalling mechanisms

Abstract Lithium has long been used in the treatment of manic disorders. Although it is a mainstay of psychiatric therapeutics, it has a very narrow therapeutic index and its acute toxicity is confined almost exclusively to the CNS. The mechanism of action of lithium is unknown, although various theories abound. These focus mainly on ideas of antagonism between lithium and other metal ions for ion-dependent physiological processes. But none of these theories explain the central selectivity of the effect . Alan Drummond describes new evidence that lithium might exert its therapeutic action by interfering with inositol lipid metabolism. The fact that cells in the CNS do not have access to plasma sources of inositol, but may instead have to rely on de-novo synthesis offers a rational explanation for its selectivity .

Drug Targeting to Monocytes and Macrophages Using Esterase-Sensitive Chemical Motifs

The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.

The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors

Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.

Hydroxamic Acid Matrix Metalloproteinase Inhibitors

It is now apparent that the matrix metalloproteinases (MMPs) play a key role in the remodeling of basement membrane that is associated with tumor metastasis, growth, and angiogenesis. Thus there is considerable interest in the design of MMP inhibitors (MMPIs) (1–6) as they promise to provide a novel noncytotoxic means of treating human cancer. Furthermore, pharmacological studies of MMPIs in animal models of human disease suggest that the potential therapeutic applications will encompass other endpoints such as arthritis and multiple-sclerosis. Recently, evidence has shown that MMP inhibitors can also reduce the production of TNF-α by inhibiting a TNF-α converting enzyme (TACE) (7–9). As a consequence, this “dual activity” may be of benefit in diseases which involve both inflammation and matrix remodeling. In this chapter we review the hydroxamic acid class of MMPIs with specific reference to the research program at British Biotech and the compounds batimastat 1 (BB-94) and marimastat 2 (BB-2516) (Fig. 1). Batimastat was the first MMPI to enter human clinical trials in cancer patients. This compound has been superseded by the orally active MMPI marimastat which is now under Phase III clinical evaluation in late-stage cancer patients. Here we present an overview of the medicinal chemistry relating to batimastat and marimastat, discuss the preclinical evaluation of compounds of this class in animal models of cancer and other human diseases and review the current clinical status for marimastat.

Pathways of dephosphorylation of 1-D-myo-inositol 1,4,5-trisphosphate in GH3 pituitary tumor cells.

Previous work in [3H]inositol-labelled GH3 pituitary tumor cells stimulated with thyrotropin-releasing hormone (TRH) reported the existence of at least ten distinct [3H]inositol-containing substances which were identified as different inositol mono-, bis- and tris-phosphate isomers [1]. Here a complete kinetic study of the dephosphorylation pathways of the second messenger Ins(1,4,5)P3 is reported in GH3 cell homogenates, identifying a new intermediate, Ins(4,5)P2, in the metabolism of the second messenger. in vitro results obtained with exogenous substrates are compared with in vivo results obtained measuring levels of the endogenous [3H]inositol-labelled isomers that participate in the dephosphorylation pathways of Ins(1,4,5)P3 in resting and TRH-stimulated GH3 cells. The effect of Li+ on the activity of the different phosphatases involved in these pathways is studied as well.