The in vivo effects of a polyamine analogue on tissue stem cell proliferation

We have studied by autoradiography the effects of 1,3-diaminopropane (DAP) upon cellular proliferation in a number of tissues in vivo in the rat. DAP is a structural analogue of the naturally occurring polyamine putrescine, and is believed to block cellular polyamine synthesis by supressing the induction of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis). The continuous infusion of DAP into rats that had been partially hepatectomised prevented the subsequent waves of spermidine and DNA synthesis from taking place in the regenerating liver. The inhibition of DNA synthesis is accounted for primarily by a block in the entry of hepatocytes into S phase and not by a reduction in the rate of DNA synthesis itself. In contrast to the regenerating liver, DAP exerted minimal effects upon the proliferation of the gut epithelium and bone marrow elements. The proliferation of stem cells of these latter tissues, which are normally in a state of rapid and continuous proliferation unlike the liver, is thus much more resistant to perturbations in polyamine biosynthesis and function. DAP is consequently unable to arrest and so protect normal rapidly proliferating tissues from damage caused by anti-cancer drugs (e.g. hydroxyurea) that kill only proliferating cells. DAP cannot therefore be employed to selectively protect normal cells but not tumour cells from cytotoxic damage according to a principle we have previously established in tissue culture.