The DNA replication mechanism has been well established for eutherian mammals (placental mammals such as humans, mice, and cattle), but not, to date, for metatherian mammals (marsupials such as kangaroos, koalas, and opossums). In this study, we found that dehydroaltenusin, a selective inhibitor of mammalian (eutherian) DNA polymerase α, clearly suppressed the growth of metatherian (opossum and rat kangaroo) cultured cells. In cultured opossum (OK) cells, dehydroaltenusin also suppressed the progression of DNA replication. These results suggest that dehydroaltenusin inhibits metatherian as well as eutherian DNA replication. Dehydroaltenusin treatment of OK cells engendered fluctuations in the numbers of chromosomes in the OK cells as well as inhibition of cell growth and DNA replication. This suggests that partial inhibition of DNA replication by dehydroaltenusin causes chromosomal instability in cultured cells.

Insulin-like growth factor-II (IGF-II) has an insulin-like effect in vitro and in vivo. Recently, mutants of IGF-II have been synthesized by the site-directed mutagenesis technique, and the structure determinants for the function of IGF-II have been studied. With the availability of the biosynthetic IGF-II and IGF-II mutants, we have investigated the hypoglycemic effect of IGFnormal rats and insulin resistant mice. When the IGF-II mutants with markedly decreased affinities for both insulin and IGF-I receptors were injected in normal rats, the blood glucose levels slightly decreased. However, when IGF-II mutant with slightly decreased affinities for both insulin and IGF-I receptors was injected, the blood glucose decreased to the same extent as with IGF-II. In insulin resistant mice, insulin did not decrease the blood glucose levels, but, the blood glucose levels decreased after IGF-I and IGF-II injection. The hypoglycemic effect of IGF-II was greater than that of IGF-I. The IGF-II mutant without affinity for IGF-II receptor but with affinities for both IGF-I and insulin receptors the same as IGF-II, caused hypoglycemia the same as IGF-I. However, the IGF-II mutant with markedly decreased affinities for both insulin and IGF-I receptors did not decrease blood glucose levels, and the IGF-II mutant with slightly decreased affinities for both insulin and IGF-II receptors slightly decreased blood glucose levels. These data indicate that the hypoglycemic effect of IGF-II is mediated mainly through insulin and/or IGF-I receptor but not IGF-II receptor. Furthermore, the data suggest that IGF-II might also be useful for the treatment of the insulin resistant status.

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