ANALOGS OF ALKYLLYSOPHOSPHOLIPIDS - CHEMISTRY, EFFECTS ON THE MOLECULAR-LEVEL AND THEIR CONSEQUENCES FOR NORMAL AND MALIGNANT-CELLS

In the search for new approaches to cancer therapy, the first alkyllys ophospholipid (ALP) analogs were designed and studied about two decade s ago, either as potential immunomodulators or as antimetabolites of p hospholipid metabolism. In the meantime, it has been demonstrated that they really act in this way. However, their special importance is bas ed on the fact that, in addition, they interfere with key events of si gnal transduction, such as hormone (or cytokine)-receptor binding or p rocessing, protein kinase C or phospholipase C function and phosphatid ylinositol and calcium metabolism. There are no strict structural requ irements for their activity. Differences in the cellular uptake or the state of cellular differentiation seem to be mainly responsible for h igher or lower sensitivities of cells towards ALP analogs. Consequence s of the molecular effects mentioned on the cellular level are cytosta sis, induction of differentiation (while in contrast the effects of kn own inducers of differentiation such as 12-O-tetradecanoylphorbol-13-a cetate are inhibited, probably as a consequence of protein kinase C in hibition) and loss of invasive properties. Already in sublytic concent rations, alterations in the membrane structure were observed, and lysi s may begin at concentrations not much higher than those causing the o ther effects described. Few ALP analogs have already entered clinical studies or are in clinical use. ALP analogs are the only antineoplasti c agents that do not act directly on the formation and function of the cellular replication machinery. Therefore, their effects are independ ent of the proliferative state of the target cells. Because of their i nterference with cellular regulatory events, including those failing i n cancer cells, ALP analogs, beyond their clinical importance, are int eresting model compounds for the development of new, more selective dr ugs for cancer therapy.