EFFECT OF ADENOSINE-ANALOGS ON THE EXPRESSION OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS FROM HUMAN DERMAL FIBROBLASTS

The effect of the cytostatic and antiviral adenosine analogues 3-deaza adenosine (c(3)Ado) and 3 deaza-(+/-)-aristeromyc in (c(3)Ari) On huma n skin fibroblasts was studied. Variables examined were cell morpholog y, viability, DNA fragmentation, expression of matrix metalloproteinas es (MMPs) and matrix metalloproteinase inhibitors (TIMPs). None of the se variables were changed when cells were exposed to c(3)Ari concentra tions ranging from 10-(5) to 10(-3) M or 10(-5) M c(3)Ado. However, la rge changes in cell morphology, viability and expression of MMPs and M MP inhibitors occurred when fibroblasts were treated with 10(-4) or 10 (-3) M c(3)Ado. Cells rounded up, shrank in volume, some detached and viability was lost without any detectable fragmentation of DNA. These changes in morphology and viability were associated with a differentia ted expression of MMPs and MMP inhibitors. A large increase in collage nase activity occurred, and depending on the concentration of the aden osine analogue and the length of treatment, this change in activity co uld be shown to be due to one or a combination of the following factor s: an increased synthesis of the collagenase protein, a decreased prod uction of MMP-1 or an increased activity of the collagenase superactiv ator, stromelysin. In contrast to this, treatment with c(3)Ado resulte d in a decreased gelatinase activity, which in part could be attribute d to an increased production of an inhibitor that seemed to affect gel atinase but not collagenase. The cellular changes induced by c(3)Ado s eemed to reflect some of the alteration in the metabolic machinery tha t appears during a drug-induced or programmed/controlled death of a de rmal cell. The different effects exerted by these two adenosine analog ues on dermal fibroblasts can at least in pare explain why c(3)Ado hav e previously been shown to be more toxic than c(3)Ari in animal models . (C) 1997 Elsevier Science Inc.