[Frontiers in Bioscience 2, d232-241, June 1, 1997]
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MODULATION OF ARA-C INDUCED APOPTOSIS IN LEUKAMAIA BY THE PKC ACTIVATOR BRYOSTATIN 1

Steven Grant.

Division of hermatology , Department of Pharmacology and Microbiology , Medical College of Virginia

Received 5/23/97; Accepted 5/28/97

2. INTRODUCTION

The last decade has witnessed a significant increase in interest in a sequence of events referred to as programmed cell death, or apoptosis. Apoptosis is known to play an important role in various aspects of cell biology, including development, immunology, and senescence, among many others. It represents an active, energy-dependent process in which a cell commits itself to an organized program of self-destruction (1). An important characteristic of apoptosis is that it can be regulated, at least in its initial stages, by a variety of genes whose products govern the activity of diverse cellular signal transduction pathways. As a consequence of this relationship, the cell death pathway is susceptible to pharmacologic manuipulation capable either of promoting or antagonizing cellular survival.

Apoptosis has particular relevance for cancer treatment, particularly that involving hematologic malignancies. Hematopoietic cells have long been known to undergo a classic apoptotic form of cell death when subjected to adverse conditions, such as growth factor deprivation (2). In contrast, tumors of epithelial cell origin tend to be relatively resistant to apoptosis, at least in its classic form (3). In leukemic cells, a very wide range of antineoplastic agents, acting by a variety of mechanisms, induce apoptosis in vitro (4). The potential importance of this phenomenon has been underscored by the identification of apoptotic cells in the peripheral blood of leukemic patients receiving cytotoxic chemotherapy (5).

The concept of modulation of drug-induced apoptosis in leukemia has a precedent in what has been referred to as biochemical modulation. In biochemical modulation, antineoplastic agents are combined in such a way as to maximize drug metabolism and achieve antitumor synergy. A classical example is the combination of an inhibitor of de novo pyrimidine biosynthesis with a nucleoside analog i.e., thymidine and 1- -D-arabinofuranosylcytosine (ara-C) (6). While similar in some respects to this approach, the strategy of modulating apoptosis has a fundamentally different basis. Thus, instead of augmenting the metabolism of the target drug, the modulating agent would act primarily to lower the threshold of the apoptotic process itself. Recentlly, interest in the development of such modulating agents has focused on the calcium- and lipid-dependent serine/threonine kinase, protein kinase C (PKC) (7). A prototypical example of this strategy has been the combination of the PKC activator bryostatin 1 and ara-C, which has been shown to exert schedule-dependent antileukemic synergism in several leukemic cell systems (8,9). The purpose of this review is to summarize what is known about the interaction between these agents, and to speculate about the basis for their synergism in light of existing knowledge. Such information could provide a rationale for the development of an entirely novel strategy for the treatment of leukemia and perhaps other hematologic and non-hemtological malignancies.