Inhibitory effect of trehalose dimycolate (TDM) and its stereoisometric derivatives, trehalose dicorynomycolates (TDCMs), with low toxicity on lung metastasis of tumour cells in mice

We examined the effect of semisynthetic trehalose-6,6'-dimycolate (TDM) and its synthetic stereoisomeric derivatives (trehalose 6,6'-dicorynomycolates : TDCMs) prepared in oil-in-water (o/w) emulsion on inhibition of lung meta stasis produced by highly metastatic murine tumour cells, colon 26-M3.1 car cinoma and B16-BL6 melanoma cells, using experimental and spontaneous metas tasis models. Intravenous (i.v.) administration of TDM (100 mu g/mouse) 1, 3 or 8 days before tumour inoculation significantly inhibited lung metastas is of colon 26-M3.1 cells, in a dose-dependent manner. Single administratio n of TDM I day after tumour inoculation also showed the therapeutic effect on experimental lung metastasis of colon 26-M3.1 cells. Similarly, multiple administrations of TDM after tumour inoculation resulted in a significant inhibition of spontaneous lung metastasis of B16-BL6 cells (on day 35), alt hough it showed no effect on suppression of tumour growth (on day 21). In c omparison of toxicity in vivo among TDM and four TDCMs such as TDCM(2R,3R), TDCM(2S,3R), TDCM(2R,3S) and TDCM(2S,3S), all of the TDCMs appeared to be less toxic than TDM itself. Furthermore, all of the TDCMs were prophylactic ally as well as therapeutically active for inhibition of lung metastasis of both colon 26-M3.1 and B16-BL6 tumour cells, showing higher inhibitory act ivity than that of TDM. In particular, TDCMs induced a marked suppression o f the growth of B16-BL6 tumour cells in vivo. These results suggest that sy stemic administration of TDM as well as TDCMs led to inhibition of tumour m etastasis and TDCMs are mon potential to suppress tumour growth and inhibit tumour metastasis than TDM. (C) 1999 Elsevier Science Ltd. All rights rese rved.