The p53 tumor suppressor gene plays an important role in DNA damage-induced apoptosis and, in general, inactivation of p53 contributes to poor response to chemotherapy. Apoptotic activity of p53 may be negatively modulated by expression of its downstream mediators, including Mdm2 and p21WAF1/CIP1. Consequently, these cellular pathways also represent potential targets for cancer therapy. This study investigated the effect of antisense oligodeoxynucleotides (ODNs), targeted against Mdm2 and p21WAF1/CIP1 on drug-mediated cell killing. Exposure of U2-OS osteosarcoma cells to DNA damaging agents, cisplatin or mitomycin C, caused upregulated expression of Mdm2 and p21WAF1/CIP1. Transient transfection of cells with antisense ODNs to Mdm2 mRNA inhibited Mdm2 protein expression and markedly enhanced apoptotic cell death induced by these drugs. Moreover, when p21WAF1/CIP1 expression was blocked by antisense transfection, drug-mediated cell killing was further accelerated. These results suggest that the enhanced expression of Mdm2 and p21WAF1/CIP1 may inhibit p53-mediated apoptosis and render cells resistant to the effects of DNA damaging agents. Consequently, antisense ODNs targeted against Mdm2 and p21WAF1/CIP1 could be employed in a potential therapeutic strategy sensitizing tumor cells to certain antineoplastic agents.

Apoptosis↗

PubMedDate not supplied

Slow learning in rats due to long-term inhalation of toluene.

Rats were exposed to toluene at the concentrations of 1,000, 4,000 and 7,000 ppm for 1 hr a day, 6 days a week for 6 months and a half; 154 days' exposure. Behavioral tests on a test battery were carried out after the termination of 154 days' exposure. The performance level of FR 1, extinction of the FR 30 schedule, wheel running activity, scores of open field test and body weight were not influenced. Slow acquisition of the timing behavior of the DRL 12 sec schedule in toluene-exposed rats was revealed: higher responses from the 1st session onwards, lower percent reinforced responses from the 1st session onwards and higher relative frequency of shorter interresponse-time (IRT) from the 9th to 12th sessions, respectively than those of the control rats. At the 33rd session onwards, the highest relative frequency of IRT of the DRL 12 sec schedule was at around 12 sec in all groups except one exposed group (7,000 ppm).

Animals↗