Retinoic acid (RA) displays potent anticarcinogenic activities that are mediated by the nuclear retinoic acid receptors (RARs). However, use of RA in oncology is limited by RA resistance acquired during carcinogenesis. Moreover, in some cancers, RA facilitates rather than inhibits growth. A clue to this paradoxical behavior was recently suggested by the findings that RA also activates PPAR␤/␦, a receptor involved in mitogenic and anti-apoptotic activities. The observations that partitioning of RA between its two receptors is regulated by two intracellular lipid-binding proteins-CRABP-II, which targets RA to RAR, and FABP5, which delivers it to PPAR␤/␦-further suggest that RA resistance may stem from the deregulation of the binding proteins, resulting in activation of PPAR␤/␦ rather than RAR. Here, we show that, in the RA-resistant mouse model of breast cancer MMTV-neu, RA indeed activates the nonclassical RA receptor PPAR␤/␦. This behavior was traced to an aberrantly high intratumor FABP5/CRABP-II ratio. Decreasing this ratio in mammary tissue diverted RA from PPAR␤/␦ to RAR and suppressed tumor growth. The data demonstrate the existence of a mechanism that underlies RA resistance in tumors, indicate that CRABP-II functions as a tumor suppressor, and suggest that the inhibition of FABP5 may comprise a therapeutic strategy for overcoming RA resistance in some tumors.cancer ͉ lipid-binding proteins ͉ nuclear receptors ͉ CRABP ͉ FABP

The mammalian circadian system has been implicated in the regulation of various biological processes including those involved in genotoxic stress responses and tumor suppression. Here we report that mice with the functional deficiency in circadian transcription factor CLOCK (Clock/Clock mutant mice) do not display predisposition to tumor formation both during their normal lifespan or when challenged by gamma- radiation. This phenotype is consistent with high apoptotic and low proliferation rate in lymphoid tissues of Clock mutant mice and is supported by the gene expression profiling of a number of apoptosis and cell cycle-related genes, as well as by growth inhibition of cells with CLOCK downregulation. At the same time, Clock mutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice. Taken together, our results demonstrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to ageing and cancer. They also highlight the existence of a complex interconnection between ageing, carcinogenesis and individual components of the circadian clock machinery.

It has been shown that genetic inhibition of p53 leads to enhanced proliferation of hematopoietic stem cells (HSCs). This could, in theory, contribute to the increased frequency of tumor development observed in p53-defcient mice and humans. In our previous work, we identified chemical p53 inhibitors (PFTs) that suppress the transactivation function of p53 and protect cultured cells and mice from death induced by gamma irradiation (IR). Here we found that when applied to bone marrow cells in vitro or injected into mice, PFTβ impeded IR-induced reduction of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) population sizes. In addition, we showed that PFTβ stimulated HSC and HPC proliferation in the absence of IR in vitro and in vivo and mobilized HSCs to the peripheral blood. Importantly, however, PFTβ treatment did not affect the timing or frequency of tumor development in irradiated p53 heterozygous mice used as a model for determination of carcinogenicity. Thus, although PFTβ administration led to increased numbers of HSCs and HPCs, it was not carcinogenic in mice. These findings suggest that chemical p53 inhibitors may be clinically useful as safe and effective stimulators of hematopoiesis.

In a small controlled study, clevudine, a potent inhibitor of hepadnaviruses, including hepatitis B virus and woodchuck hepatitis virus, suppressed hepatitis delta virus (HDV) viremia in chronically infected woodchucks. Suppression was correlated with the marked reduction of woodchuck hepatitis virus surface antigen in individual animals, consistent with the concept that repression of surface antigen expression may be a useful antiviral strategy for HDV.Type D hepatitis is caused by infection with hepatitis D (delta) virus (HDV), an obligate subviral satellite of hepatitis B virus (HBV) (9). The HDV virion is composed of a ribonucleoprotein core and an envelope formed by the surface antigen protein (HBsAg) of HBV (1-3). The envelope is the sole helper function provided by HBV, in that HDV is able to replicate within cells in the absence of HBV (13) but requires HBsAg for packaging and release of HDV virions (28, 37) as well as for infectivity (31).Chronic type D hepatitis, similar to chronic HBV infection, is typically characterized by necroinflammatory lesions, but it is more severe and frequently progresses rapidly to cirrhosis and liver failure, accounting for a disproportionate association of chronic HDV infection with terminal liver disease and an indication for liver transplantation (26, 30). There is currently no generally accepted effective therapy for type D hepatitis (see reference 21 for a review), and liver transplantation is the only option for the associated end-stage liver disease (36). Exceptionally high doses of alpha interferon have been, at best, moderately successful in treating some cases of type D hepatitis (6,10,27,34). Acyclovir enhances HDV replication in vitro. Ribavirin does not significantly affect virologic or biochemical parameters, and there were severe side effects in clinical trials. Synthetic analogs of thymosin have been ineffective in the treatment of HDV infection (21).The dependence of HDV on HBV could suggest that successful treatment of HDV infection would follow successful treatment of the supporting HBV infection. Unfortunately, this does not always appear to be the case. Although treatment of chronic HBV carriers with lamivudine (␤-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine) leads to decreased levels of HBV in serum and improved liver histology (5,14,20), in patients with chronic delta hepatitis prolonged lamivudine therapy neither lowers HDV RNA levels nor ameliorates disease activity, even though HBV viremia is reduced (15,35). Similarly, treatment with famciclovir was not effective against HDV infection (38). The most likely explanation for the failure of these treatments to affect HDV is that HDV requires the HBsAg function of HBV, and lamivudine treatment does not typically reduce HBsAg levels. We therefore sought to determine whether HDV could be inhibited by an anti-HBV therapeutic agent that dramatically reduces HBsAg levels.Woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck, represent a useful model of HBV-induced disease that is predictive of nuc...