A study on the potential of cyclosporin A in combination with α-difluoromethylornithine as an antitumour therapy

• Main Author: McLachlan, G.
• Published: University of Aberdeen 1993
• Subjects: 615.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.593080

We investigated the effects of cyclosporin A (CsA) and α-difluoromethylornithine (DFMO) <i>in vivo</i>, on survival, tumour progression and polyamine levels of rats bearing the Roser leukaemia (RL), and in more detail <i>in vitro</i> using the MOLT-4 human T-lymphoblastic leukaemia cell line. CsA (25mg/kg/day) and DFMO (3% w/v in drinking water) markedly reduced the number of circulating lymphoblasts in tumour-bearing rats but only DFMO prolonged survival. A further decrease in lymphoblasts, but no further increase in survival resulting from combination therapy. Of the two drugs, only DFMO treatment inhibited polyamine biosynthesis <i>in vivo</i>. DFMO and CsA both inhibited the growth of MOLT-4 cells <i>in vitro</i>. Unlike DFMO, CsA treatment did not deplete polyamines, neither were its effects reversed by the addition of exogenous putrescine. Although the effects of simultaneous combination on growth and polyamine content were no better than monotherapy, an alternative regime of drug addition involving 48h pretreatment with DFMO, prior to addition of CsA, inhibited cell growth by more than either drug alone. We observed that the uptake of CsA is initially rapid, but gradually decreases. In the presence of DFMO this decline in the rate of uptake of CsA was delayed leading to increased cellular accumulation of CsA. Ornithine decarboxylase (ODC) activity in MOLT-4 cells was inhibited by DFMO. Although CsA (2.5 & 5μg/ml) decreased ODC activity after 24h, after 48h the inhibition was markedly less. Treatment of cells with methylthiopropylamine led to induction of ODC. DFMO prevented this induction and almost completely inhibited the existing ODC, whereas CsA only prevented the rise in ODC. We compared the antitumour effects of CsA with those of the immunosuppressant, FK-506, since its immunosuppressive action is reported to be identical to that of CsA, but is approximately 100-fold more potent. We found that FK-506 had less effect on growth of MOLT-4 cells than CsA even at higher doses, nor did it inhibit basal or induced ODC, suggesting that CsA had a distinct antiproliferative activity.