NC381, a novel anticancer agent, arrests the cell cycle in G0-G1 and inhibits lung tumor cell growth in vitro and in vivo.

Although clotrimazole (CLT), an antifungal drug, inhibits tumor cell proliferation and angiogenesis, its clinical application is hampered by significant hepatotoxicity due to the presence of an imidazole moiety. In our attempts to develop CLT analogs that are devoid of imidazole and are as efficacious as CLT, one pharmacophore designated NC381 was generated and shown to inhibit tumor cell growth via a mechanism similar to that of CLT. In vitro, treatment of NCI-H460 nonsmall cell lung cancer (NSCLC) cells with NC381 inhibited growth in a time-dependent manner. Flow cytometric analysis demonstrated that the decrease in cell growth was associated with inhibition of cell cycle progression at the G(1)-S phase transition, resulting in G(0)-G(1) arrest. There was a concomitant inhibition of cyclin D1 expression and subsequent reduction in the formation of the cyclin D1-CDK4 complex. Consistent with a decrease in the cyclin D1-CDK4 complex, NC381 treatment resulted in significant inhibition of pRb phosphorylation. There also were changes in the activity of cell cycle-related proteins, including p16(Ink4) and p27(Kip1). Together, these results are consistent with a model in which NC381 arrests cell cycle progression via inhibition of the pathway that promotes exit from the G(1) phase of the cell cycle. Furthermore, the clinical applicability of NC381 was evaluated in an in vivo murine xenograft model of human NSCLC (NCI-H460). NC381 treatment resulted in significant inhibition of tumor growth. Given the poor prognosis and the limited treatment options available, the present results underscore the potential of NC381 in the treatment of human NSCLC.

Adenovirus-mediated ribonucleotide reductase R1 gene therapy of human colon adenocarcinoma.

Ribonucleotide reductase is the enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides for DNA synthesis. Ribonucleotide reductase is a multisubunit complex containing two polypeptides, R1 and R2. In addition to catalytic and allosteric regulatory functions, the R1 subunit appears to act as a novel tumor suppressor. Previous studies demonstrated that overexpression of mouse R1 resulted in suppression of tumorigenicity and metastatic potential, whereas expression of antisense RNA, complementary to R1 mRNA, increased anchorage-independent growth of ras-transformed NIH 3T3 cells. The current study investigated the potential of R1 gene therapy for human cancer using a recombinant adenovirus encoding the human R1 gene (rAd5-R1). Recombinant viruses were constructed by FLP-mediated site-specific recombination and demonstrated high infectivity of a human colon carcinoma cell line (Colo320 HRS), as assessed by expression of a viral encoded beta-Gal gene (rAd5-LacZ). R1mRNA and protein were overexpressed in Colo320 HRS cells infected with rAd5-R1 compared with untreated or rAd5-LacZ-infected cells. Infection with rAd5-R1 inhibited Colo320 HRS cell proliferation, in vitro, in a time- and dose-dependent manner. When Colo320 HRS cells were treated with rAd5-R1, before injection into CD-1 mice, there was complete inhibition of tumor growth compared with treatment with rAd5-LacZ. Furthermore, intratumoral injection of rAd5-R1 into Colo320 HRS tumor xenografts inhibited tumor growth in CD-1 mice compared with rAd5-LacZ treated mice (P = 0.0001). These results demonstrate gene-specific antitumor effects of R1 and suggest that rAd5-R1 gene therapy has the potential to improve currently available treatments for colon cancer.

[The effect of dietary intervention on lipidemia in school-aged children].

OBJECTIVE: To evaluate the effect of dietary intervention on lipidemia in school-aged children. METHODS: The levels of serum lipids profile were detected in 316 school children aged 7 - 11, from those the subjects of dietary intervention were selected by total cholesterol level above 4.26 mmol/L or low density lipoprotein cholesterol level above 2.23 mmol/L. The subjects were randomly divided into intervention group (120) and control group (40). Children in intervention group were fed with low-cholesterol and low-saturated fatty acid diet, and the control group with normal diet. The duration of intervention was three months. Before and after the intervention, the food intakes, health-related questionnaire and physical examination (height, weight, skinfolds thickness and so on) in the two groups were studied. RESULTS: Compared with the control group, serum cholesterol levels of children under intervention were not significantly changed (TC: 4.64 vs 4.68 mmol/L, P > 0.05; LDL-C: 2.66 vs 2.62 mmol/L, P > 0.05), but the apoA(1) level increased from 1,378.4 mg/L to 1,441.3 mg/L (P < 0.05). There were no changes for any serum lipids indexes in the control group while the dietary intakes of energy, cholesterol and SFA decreased markedly in the intervention group, with the percent of energy from fat decreased from 40.7% to 31.2% and SFA below to 10% (7.7%). Along with the increase of the scores of knowledge on health among children under intervention, the living and eating habit improved (the total scores increased from 24.6 to 27.4, P < 0.05). The increase of height was not significantly different between the two groups. CONCLUSION: With the family-based high-risk intervention strategy on the dietary adjustment, the knowledge on health, living and eating habit could be effectively improved in children with lipidemia. However, further research about the intervention effect on the serum cholesterol levels by strengthening the interventional degree, needs to be further studied.