Fish oil and cell proliferation kinetics in a mammary carcinoma tumor model

In vivo bromodeoxyuridine (BrdUrd) labelling and bivariate BrdUrd/DNA analysis was used to evaluate cell cycle kinetics in a rat tumor model known to be sensitive to dietary fatty acid manipulation. Fish oil supplementation significantly reduced the rate of BrdUrd movement relative to DNA content, indicating prolongation of the DNA replication time. This finding, which accounted for most of the decrease in tumor growth rate in the fish oil-fed group, represents the first description of an alteration in S phase duration by an extrinsic factor. The significance of this finding is discussed in relation to current understanding of cell cycle regulation. Fish oil feeding is associated with slower growth rate in certain tumors (1,2). According to current concepts of cellular proliferation (3), regulation of growth by extrinsic factors is thought to precede the S phase. This statement is based on the notion that, within a given cell type, DNA replication time (S phase duration) is constant (4-6). Extensive evidence also supports an on/off mechanism of cell cycle regulation at the level of entry into the S phase (3). In this report, we present evidence showing, for the first time, that the S phase duration of fat-responsive tumor cells can be altered by dietary manipulation of fatty acids. Furthermore, these differences in S phase duration appear to account for all the in vivo variation in tumor growth resulting from fish oil feeding. Although the mechanism of this phenomenon remains unclear, our observations support increasing evidence for a regulatory step at the level of the nucleus. They are also important for understanding the relationship between dietary fat and tumor growth.