Influence of cyclosporin a and α-difluoromethylornithine, an inhibitor of polyamine biosynthesis, on two rodent T-cell cancers in vivo
✍ Scribed by L. M. Smart; G. Maclachlan; H. M. Wallace; A. W. Thomson
- Publisher
- John Wiley and Sons
- Year
- 1989
- Tongue
- French
- Weight
- 531 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
We have examined the influence of cyclosporin A (CsA), administered together with the polyamine antimetabolite, o-difluoromethylornithine (DFMO), on growth of the Roser acute T-cell leukaemia in PVG rats and on growth of the EL4 lymphoma in C57BU6 mice. CsA or DFMO alone, administered from the time of tumour injection, markedly reduced numbers of circulating lymphoblasts in leukaemic rats, although survival was prolonged only in those animals given DFMO. Drug combination further reduced blood-borne tumour cells, but had no additional effects on tumour growth within organs or on host survival, compared to that achieved with DFMO treatment alone. Neither CsA nor DFMO, administered from the time of tumour-cell injection, nor both drugs in combination, affected peritoneal growth of the EL4 lymphoma or organ infiltration. Host survival was prolonged by DFMO. As anticipated, DFMO inhibited polyamine synthesis in vivo, but the observed anti-tumour effect of CsA was not accompanied by an alteration in polyamine biosynthesis. By reducing polyamine synthesis, however, DFMO may enhance the vulnerability of those malignant T cells which are susceptible to the as yet unexplained selective inhibitory action of CsA in vivo.
MATERIAL AND METHODS
Animals
Inbred male PVG rats (mean weight 250 g) purchased from Harlan Olac, Bicester, UK, were used. Mice were inbred C57BL/6 males (mean weight 25 g) purchased from Banton and Kingman, Hull, UK.
Animals were maintained in a light-, air-and tempexatureregulated environment and received CRM diet (Greef, Croydon, UK) with tap water ad libitum.
CsA
CsA (batch 161412) Sandoz, Basel, Switzerland, was provided in powder form and dissolved initially in anhydrous ethanol to which were added 9 parts of olive oil. The solution was mixed thoroughly and administered as follows: (a) rats received a dose of 25 mg/kg or 18.75 mg/kg (0.1 m1/100 g body weight) by gavage; (b) mice were given a dose of 75 mg/kg (0.4 ml/lOO g body weight) by S.C. injection into the flank. CsA solution was stored in the dark for no more than 3 days.
a-Dzjluoromethy lornithine
D-L-a-difluoromethylornithine (DFM0)-HClH,O, synthesized at the Merrell Dow Research Institute, Strasbourg, France, was a kind gift from the manufacturers. Powdered DFMO was dissolved in drinking (tap) water (2-3% w/v). Mice received a mean dose of 6.7 g/kg/day throughout the experimental period, whilst in rats, monitoring of fluid intake proved that it was necessary to increase the DFMO concentration from 2 to 3% (w/v) from day 7, in order to maintain doses of 2.5-3 g/kg/day.
Roser acute T-cell leukaemia
The Roser T-cell leukaemia, described by Dibley et al. (1975), was kindly provided by Dr. H. Jackson, Department of 3To whom reprint requests should be sent.