Tumour-inhibiting Action of 1 : 6-Dimethanesulphonyl-D-mannitol

Abstract

EXTENSIVE clinical experience with ‘Myleran’ (I, n= 4) in the treatment of chronic myeloid leukæmia¹ has shown that when over-dosage is avoided the drug is free from side-effects. On the other hand, other alkylating agents which are used clinically, namely, ethyleneimine derivatives and nitrogen mustards, usually cause some side-effects. This contrast may be attributable to a different mechanism of action for ‘Myleran’ and for the other alkylating agents. Evidence for this difference arises from comparison of the effects of ‘Myleran’ and a mustard (chlorambucil) on rat bone-marrow² and from a similar comparison where, when the drugs were used clinically in leukæmia, there was no enhanced excretion of uric acid after administration of ‘Myleran’ although nitrogen mustards and tri-ethylenemelamine caused a significant rise in uric acid excretion³. ‘Myleran’ and its congeners (I), while they inhibit experimental tumours, cause a marked depression of bone-marrow function and cannot therefore be considered suitable for the treatment of solid tumours in man. In the ‘Myleran’ series there is evidence that variations in neutrophil-depressing and also in tumour-inhibitory activity may depend very much on the ratio between the solubility of the particular compound in water and in ether⁴. In the hope that a very large relative increase in water solubility might possibly minimize the bone-marrow depressing properties of the ‘Myleran’ series while leaving unaffected tumour-inhibitory activity together with the apparent clinical virtues attributable to the ‘Myleran’ type of action, we decided to modify the series by the insertion of hydroxy groups in the polymethylene chain. Bis-l :6-2′-chloroethylamino-1:6-dideoxy-D-mannitol (II) had been made because it was a type of nitrogen mustard which it was thought might inhibit glycolysis⁵. The fact that its tetrahydroxylated hexamethylene chain structure was consistent with tumour-inhibiting activity led us to choose 1 : 6-dimethanesulphonyl-D-mannitol (III) as the first member of our new series.