SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol.

The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study the function of SirT1 in susceptibility to tumorigenesis.

4-1BB functions as a survival factor in dendritic cells.

4-1BB (CD137) is expressed on dendritic cells (DCs) and its biological function has remained largely unresolved. By comparing 4-1BB-intact (4-1BB(+/+)) and 4-1BB-deficient (4-1BB(-/-)) DCs, we found that 4-1BB was strongly induced on DCs during the maturation and that DC maturation was normal in the absence of 4-1BB. However, DC survival rate was low in the absence of 4-1BB, which was due to the decreased Bcl-2 and Bcl-x(L) in 4-1BB(-/-) DCs compared with 4-1BB(+/+) DCs after DC maturation.

IFN-gamma-indoleamine-2,3 dioxygenase acts as a major suppressive factor in 4-1BB-mediated immune suppression in vivo.

It has been reported that 4-1BB triggering in vivo selectively suppressed the recall response of staphylococcal enterotoxin A (SEA)-specific CD4(+) T cells, in which CD8(+) T-derived TGF-beta was involved. Here, we have examined an alternative mechanism for the 4-1BB-mediated CD4(+) T suppression, as the neutralization of TGF-beta is only effective in rescuing the SEA-specific recall response at high cellular concentrations. We show that this selective suppression of CD4(+) T cells by 4-1BB triggering in vivo is mediated mainly by induction of indoleamine 2,3-dioxygenase (IDO) in an IFN-gamma-dependent manner.

Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy.

Chemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8(+) T cells, the 4-1BB-dependent expansion and differentiation of which into IFN-gamma-producing CD11c(+)CD8(+) T cells was enhanced by CTX.

Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity.

Anti-4-1BB and cisplatin showed synergistic anticancer effects in the CT-26 colon carcinoma model, producing complete regression in >60% of mice with either preventive or therapeutic treatment. The tumor-free mice formed long-lasting CD8(+) T cell-dependent tumor-specific memory. Anti-4-1BB induced rapid repopulation of T and B cells from cisplatin-mediated lymphopenia and differentiation and expansion of IFN-gamma(+)CD11c(+)CD8(+) T cells.

sirt1-null mice develop an autoimmune-like condition.

The sirt1 gene encodes a protein deacetylase with a broad spectrum of reported substrates. Mice carrying null alleles for sirt1 are viable on outbred genetic backgrounds so we have examined them in detail to identify the biological processes that are dependent on SIRT1. Sera from adult sirt1-null mice contain antibodies that react with nuclear antigens and immune complexes become deposited in the livers and kidneys of these animals.

SirT1 regulates energy metabolism and response to caloric restriction in mice.

The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food.

Modulation of response to tumor therapies by the extracellular matrix.

The composition of the extracellular matrix in tumors is vastly different from that found in the normal tissue counterparts. As the extracellular matrix can signal to cells via integrin binding and activation, which is known to modulate cell proliferation, survival and migration, it may influence the response of both tumor and endothelial cells to anticancer therapies. Certain tumor-associated extracellular matrix proteins have been shown to confer resistance to chemotherapeutic drugs, radiation and anti-angiogenic factors.

ErbB2 overexpression in an ovarian cancer cell line confers sensitivity to the HSP90 inhibitor geldanamycin.

ErbB2 is overexpressed in 25-30% of breast and ovarian cancers, correlates with poor prognosis and lower survival and has also been associated with chemoresistance. We have established an isogenic pair of human ovarian cells that differ only in the expression of erbB2 protein in order to elucidate the role of the protein in determining cellular sensitivity to various drugs and agents. These included cisplatin and paclitaxel, the main drugs used in the treatment of ovarian cancer, and also various signal transduction inhibitors affecting the ras and P13K pathways.

A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity.

The telomerase complex is responsible for telomere maintenance and represents a promising cancer therapeutic target. We describe herein the antitelomerase and antitumor properties of a small-molecule compound designed by computer modeling to interact with and stabilize human G-quadruplex DNA, a structure that may form with telomeric DNA, thereby inhibiting access to telomerase. The 3,6,9-trisubstituted acridine 9-[4-(N,N-dimethylamino)phenylamino]-3,6-bis(3-pyrrolodinopropionamido) acridine (BRACO19) represents one of the most potent cell-free inhibitors of human telomerase yet described (50% inhibitory concentration of 115 +/- 18 nM).

N-(Hydroxymethyl) melamines.

1. The N-(hydroxymethyl) melamines are analogs of the antitumor agent hexamethylmelamine (HMM) which do not require bioactivation to exert their antitumor effects. 2.