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PubMedDate not supplied

Poly (ADP-ribose) polymerase (PARP) is essential for sulfur mustard-induced DNA damage repair, but has no role in DNA ligase activation.

Concurrent activation of poly (ADP-ribose) polymerase (PARP) and DNA ligase was observed in cultured human epidermal keratinocytes (HEK) exposed to the DNA alkylating compound sulfur mustard (SM), suggesting that DNA ligase activation could be due to its modification by PARP. Using HEK, intracellular 3H-labeled NAD+ (3H-adenine) was metabolically generated and then these cells were exposed to SM (1 mM). DNA ligase I isolated from these cells was not 3H-labeled, indicating that DNA ligase I is not a substrate for (ADP-ribosyl)ation by PARP. In HEK, when PARP was inhibited by 3-amino benzamide (3-AB, 2 mM), SM-activated DNA ligase had a half-life that was four-fold higher than that observed in the absence of 3-AB. These results suggest that DNA repair requires PARP, and that DNA ligase remains activated until DNA damage repair is complete. The results show that in SM-exposed HEK, DNA ligase I is activated by phosphorylation catalysed by DNA-dependent protein kinase (DNA-PK). Therefore, the role of PARP in DNA repair is other than that of DNA ligase I activation. By using the DNA ligase I phosphorylation assay and decreasing PARP chemically as well as by PARP anti-sense mRNA expression in the cells, it was confirmed that PARP does not modify DNA ligase I. In conclusion, it is proposed that PARP is essential for efficient DNA repair; however, PARP participates in DNA repair by altering the chromosomal structure to make the DNA damage site(s) accessible to the repair enzymes.

Apoptosis↗
PubMed2005

Hypoxia inducible factor-1: a novel target for cancer therapy.

Hypoxia develops in the majority of solid tumors due to the inability of the existing vascular system to supply the growing tumor mass with adequate amounts of oxygen. A large body of clinical evidence suggests that intratumoral hypoxia correlates with the elevated aggressive behavior of cancer cells and their resistance to therapy, leading to poor patient prognoses. A heterodimeric transcription factor, hypoxia inducible factor-1 (HIF-1), has been shown to orchestrate a large number of molecular events required for the adaptation of tumor cells to hypoxia. Therefore, HIF-1 has become an attractive target for the development of anti-cancer drugs. Here, we highlight some of the recently developed small-molecule inhibitors of HIF-1 function. These drugs disrupt the HIF-1 signaling pathway through a variety of mechanisms, including the inhibition of HIF-1alpha protein synthesis, stabilization, nuclear translocation and HIF-1 transactivation of target genes.

Benzopyrans↗
PubMed1980

The immunosuppressive effect of beta-[1-phenyl-5-bis(beta-chloroethyl)-aminobenzimidazolyl-(2)]-DL-alanine (ZIMET 3164) on cell-mediated immunity in mice.

The potential immunosuppressive drug beta-[1-Phenyl-5-bis(beta-chloroethyl-5-amino-benzimidazolyl-(2)]-DL-alanine (ZIMET 3164) was tested for its effect on cell-mediated immunity. The models "skin grafting" and "contact hypersensitivity" were used. --The results showed a marked prolongation of the mean survival time of the skin grafts and also a high depression of the contact hypersensitivity (delayed hypersensitivity) to picryl chloride. The immunosuppressive efficacy of ZIMET 3164 was higher than that of the reference compound cyclophosphamide.

Animals↗
PubMed1988

The depletion of rat cortical norepinephrine and the inhibition of [3H]norepinephrine uptake by xylamine does not require monoamine oxidase activity.

Inhibition of monoamine oxidase A through pretreatment of rats with clorgyline (10 mg/kg ip) or the pro-drug MDL 72,394 (0.5 mg/kg ip) did not block the amine-depleting action of xylamine (25 mg/kg ip). Xylamine treatment resulted in a loss of approximately 60% of the control level of norepinephrine in the cerebral cortex. A 1-hr pretreatment, but not a 24-hr pretreatment, with the monoamine oxidase B inhibitor, L-deprenyl (10 mg/kg ip), prevented the depletion of norepinephrine by xylamine. In addition, pretreatment with MDL 72,974 (1.25 mg/kg ip), a monoamine oxidase B inhibitor without amine-releasing or uptake - inhibiting effects, did not protect cortical norepinephrine levels. Inhibition of monoamine oxidase by either MDL 72,974 or MDL 72,394 did not prevent the inhibition of [3H]norepinephrine uptake into rat cortical synaptosomes by xylamine. These data indicate that monoamine oxidase does not mediate the amine-releasing or uptake inhibiting properties of xylamine. The protection afforded by L-deprenyl following a 1-hr pretreatment most probably was due to accumulation of its metabolite, L-amphetamine, which would inhibit the uptake carrier. A functional carrier is required for depletion since desipramine (20 mg/kg ip) administered 1 hr prior to xylamine, was also able to prevent depletion of norepinephrine.

Allyl Compounds↗
PubMed1991

[The action of an alkylating analog of hexadecamethonium on neuromuscular transmission in the frog].

The treatment of m. cutaneus pectoris-n. pectoralis preparations with 0.5 microM of alkylating derivate of hexadecamethonium, hexadecamethylene-bis-methylchloroethylamine, led to irreversible decrease of the amplitude of EPPs. The decrease was shown to be of a postsynaptic nature. After pretreatment of the neuromuscular preparations with alkylating derivate the effects of cholinesterase inhibitors were strongly diminished.

Alkylating Agents↗