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 alkyllysophospholipid (ALP) analogs were designed and studied about two decades ago, either as potential immunomodulators or as antimetabolites of phospholipid metabolism. In the meantime, it has been demonstrated that they really act in this way. However, their special importance is based on the fact that, in addition, they interfere with key events of signal transduction, such as hormone (or cytokine)-receptor binding or processing, protein kinase C or phospholipase C function and phosphatidylinositol and calcium metabolism. There are no strict structural requirements for their activity. Differences in the cellular uptake or the state of cellular differentiation seem to be mainly responsible for higher or lower sensitivities of cells towards ALP analogs. Consequences of the molecular effects mentioned on the cellular level are cytostasis, induction of differentiation (while in contrast the effects of known inducers of differentiation such as 12-O-tetradecanoylphorbol-13-acetate are inhibited, probably as a consequence of protein kinase C inhibition) and loss of invasive properties. Already in sublytic concentrations, alterations in the membrane structure were observed, and lysis may begin at concentrations not much higher than those causing the other effects described. Few ALP analogs have already entered clinical studies or are in clinical use. ALP analogs are the only antineoplastic agents that do not act directly on the formation and function of the cellular replication machinery. Therefore, their effects are independent of the proliferative state of the target cells. Because of their interference with cellular regulatory events, including those failing in cancer cells, ALP analogs, beyond their clinical importance, are interesting model compounds for the development of new, more selective drugs for cancer therapy.
Brachwitz
H
H
Department of Hematology and Oncology, Klinikum Steglitz, Freie Universität Berlin, Germany.
Vollgraf
C
C
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D010743:Phospholipids; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium