Spiegelman bm

Irisin, a skeletal-muscle secreted myokine, facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In this study, we investigated whether irisin directly regulates osteoclasts. In vitro, irisin (2-10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; however, this increase was blocked by a neutralizing antibody to integrin αV β5 . Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating 'clastokines'...

The effect of uridine on the incorporation of 5-fluorouracil into RNA and the inhibition of DNA synthesis by the FdUMP block of thymidylate synthetase was studied in the CD8F1 murine mammary carcinoma system. The administration of exogenous uridine resulted in about a one third reduction of 5-fluorouracil in RNA of tumor and normal tissues. However, unlike thymidine, uridine was unable to reverse the early, partial inhibition of DNA synthesis. The amount of fluorouridine nucleotides and (5-fluorouracil)RNA formed in various tissues correlates with the level of orotate phosphoribosyl transferase activity suggesting that the major pathway for activation of 5-fluorouracil to nucleotide form in these tissues is via phosphoribosyl transferase...

Because of the association between the incorporation of 5-fluorouracil (FUra) into RNA and cytotoxicity, uridine was examined for potential selective reduction of host toxicity. Male BALB/c x DBA/2 F1 mice (tumor free or bearing advanced colon tumor 26) were used. Two uridine schedules (each beginning 2 hr after FUra) have been successful: (a) uridine at 800 mg/kg every 2 hr for three doses followed 18 hr later by uridine at 800 mg/kg every 2 hr for four doses; or (b) two doses of uridine at 3500 mg/kg separated by an 18-hr interval...

This review summarizes a body of information suggesting that proper metabolic modulation with certain metabolites can sensitize tumor cells to anti-metabolites, and others can de-sensitize (i.e. protect) normal cells from the toxicity of anti-metabolites. This new approach offers the possibility of increasing the selectivity of drug therapy, with the promise of a real advance in cancer chemotherapy. The metabolite thymidine (TdR), long used as a cell synchronizing agent, is known to exert this effect in vitro by metabolic modulation of a number of enzymes in the salvage pathway to DNA synthesis...

Although 5-fluorouracil (FUra) is readily incorporated into RNA, the possibility of its being incorporated into DNA in substantial amounts has only recently been recognized. Examination of nucleic acids prepared from tumor-bearing BALB/c X DBA/8 F1 mice labeled with [3H]FUra in vivo revealed very little alkali-stable, acid-precipitable radioactivity in tumor and only small amounts in intestine. However, substantial amounts were detected in bone marrow. Pretreatment of mice with low-dose thymidine (500 mg/kg) increased the incorporation of FUra into RNA but did not change the amount incorporated into alkali-stable material...

Doses of N-(phosphonacetyl)-L-aspartic acid (PALA) lower than those required for therapeutic activity against the spontaneous murine breast tumor (BALB/c X DBA/8 F1) were found to produce significant depression in uridine triphosphate pools in the tumor. Using such low, nontherapeutic, but biochemically active doses of PALA in combination with 5-fluorouracil (FUra(, it was possible to maintain the dose of FUra at its full maximum tolerated single agent dose. In comparison with the maximum tolerated dose of FUra alone, the combination of FUra plus low-dose PALA produced a significant increase in the level of tumor FUra-containing RNA, only a slight increase in intestinal FUra-containing RNA, and no increase in bone marrow FUra-containing RNA...

Partially purified preparations of mouse interferon, administered during the 2-day period following the administration of a toxic dose of 5-fluorouracil (FUra), yielded significant protection from mortality in BALB/c X DBA/2 F1 mice. Protection against FUra-induced toxicity was also observed when the interferon inducer polyinosinic-polycytidylic acid (poly I X poly C) was administered with FUra. The temporal relationship between the administration of poly I X poly C and FUra was found to be a critical determinant of the intensity of toxic manifestations...

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