Oncogene and tumor suppressor gene expression changes in the peripheral blood leukocytes of patients with colorectal cancer.

AIMS AND BACKGROUND: The mortality of colorectal cancer continues to stagnate despite the development of new therapeutic approaches. Therefore, identifying high-risk population groups could contribute to the prevention of a considerable part of deaths caused by colorectal tumors. METHODS: Fifty patients with colon cancer and 50 patients with other, nonmalignant diseases were selected for the study. Expression of the c-myc, Ha-ras and p53 genes was determined in the peripheral leukocytes of the participants. RESULTS: Marked elevations of the expression of all three investigated genes were seen in the colon cancer patients when compared to the controls. CONCLUSIONS: Our investigations showed that increases in the expression of c-myc, Ha-ras and p53 genes can be demonstrated in the peripheral leukocytes of colon cancer patients. By applying our method to clinical investigations, individuals with a high risk of having developed colon cancer may be identified and early diagnosis may be established.

In vivo effects of afobazole (2-mercaptobenzimidazole derivative) on the 7,12-dimethylbenz [alpha]anthracene-induced oncogene and suppressor gene expression.

BACKGROUND: Afobazole, a new 2-mercapto-benzimidazole derivative, exhibited antimutagenic activity in chromosome aberration tests and antioxidant properties. The aim of this study was to demonstrate the potential chemopreventive effect of afobazole on the level of early biological effects by analysing changes in oncogene and tumor suppressor gene expression. MATERIALS AND METHODS: Single intraperitoneal (i.p.) treatment with 7,12-dimethylbenz[alpha]anthracene (DMBA) combined with afobazole was administered to CBA/Ca (sensitive H-2K haplotype) female mice. The expression of Ha-ras and p53 was determined in the vital organs (liver, spleen, lung, kidney, thymus, lymph nodes and bone marrow) 24, 48 and 72 hours later. RESULTS: Coadministration of afobazole and DMBA resulted in a decrease of DMBA-induced overexpression of Ha-ras and p53. Reduction of the DMBA-induced gene expression was most striking when afobazole was given in parallel with DMBA. DISCUSSION: Our results strengthen the previous assumption, which was based on in vitro results, that afobazole has a chemopreventive effect in vivo.

All-trans retinoic acid (ATRA) suppresses transcription of human papillomavirus type 16 (HPV16) in a dose-dependent manner.

Earlier we found that SiHa cervical squamous carcinoma cells that harbor HPV type 16 respond to ATRA treatment in a dose-dependent manner: high-dose (10(-5)-10(-4) M) but not low-dose (10(-7)-10(-6) M) ATRA induced growth arrest. Growth of HPV-infected cells is highly dependent on the expression of the viral E6/E7 proteins. Thus, targeting expression of the viral E6/E7 genes might influence growth properties of HPV-infected cells. Here, we demonstrated that high-dose ATRA inhibited expression of HPV16 E7 through suppression of the HPV16 promoter (p97) activity. Gelshift assay (EMSA) revealed that binding of the AP-1 transcription factor to an oligonucleotide originated from the HPV type 16 promoter was diminished after high-dose, but not low-dose ATRA treatment. This suggests that high-dose ATRA suppresses HPV 16 promoter activity, at least in part, via a decreased AP-1 binding. Our data might be useful in treatment of cervical dysplasias and/or carcinomas.

Polymorphisms of glutathione-S-transferase and arylamine N-acetyltransferase enzymes and susceptibility to colorectal cancer.

BACKGROUND: Glutathione-S-transferases (GSTs) and N-acetyltransferases (NATs) are involved in the metabolism of a wide range of carcinogenic chemicals. Allelic polymorphism of these enzymes is associated with variations in enzyme activity, hence it may affect the concentration of activated carcinogenic chemicals in the body. Previous studies suggest a possible cancer risk-modifying effect of these allelic polymorphisms, but the results are still controversial. We evaluated the effect of GSTM1, GSTT1, GSTP1, NAT1 and NAT2 enzymes on individual susceptibility to colorectal cancer, with particular attention to possible interactions between the studied genotypes. MATERIALS AND METHODS: Five hundred colorectal cancer patients and 500 matched cancer-free controls were included in the study. The allelic polymorphisms of GSTM1, GSTT1 and GSTP1, NAT1 and NAT2 enzymes were determined by PCR-based methods, from peripheral blood leukocytes, and allelic distributions were compared between colorectal cancer patients and controls. RESULTS: The GSTM1 0 allele (OR: 1.48, 95% CI: 1.15-1.92) and rapid acetylator genotypes of NAT2 (OR: 1.52, 95% CI: 1.17-1.98) were associated with an elevated risk No statistically significant correlation between NAT1, GSTT1, GSTP1 genotypes and colorectal cancer was found. Remarkably increased risk was associated with the GSTM1 0 allele--NAT2 rapid acetylator genotype combination (OR: 2.39, 95% CI: 1.75-3.26) and with the GSTM1 0 allele--NAT2 and NAT1 rapid acetylator triple combination (OR: 3.28, 95% CI: 2.06-5.23). Carrying 4 or 5 putative "high-risk" alleles substantially increased the risk of colorectal cancer (OR: 3.69, 95% CI: 2.33-5.86). CONCLUSION: The genotype of certain metabolizing enzymes affects the risk for colorectal cancer. This effect is particularly important when certain allelic combinations are studied. In the near future, individual level risk assessment may be reached by further increasing the number of studied polymorphisms, combining them with traditional epidemiological risk factors.