Altered expression of c-myc, p16 and p27 in rat colon tumors and its reversal by short-term treatment with chemopreventive agents.
Modulation of gene expression in tumors has the potential of being a surrogate end-point biomarker for chemoprevention. Thus, we determined the modulation by chemopreventive agents of the protein and mRNA expression of genes in rat colon tumors. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane. Forty-seven weeks later, they received aspirin (600), calcium chloride (50 000), 2-(carboxyphenyl) retinamide (2-CPR, 315), alpha-difluoromethylornithine (DFMO, 3000), piroxicam (200), quercetin (33 600), 9-cis retinoic acid (9-cis RA, 30), rutin (3000), or sulindac (280) in their diet at the indicated mg/kg concentration for 7 days and were then killed. In colon tumors relative to the mucosa, the protein and mRNA levels of c-myc were increased, while the levels of p16 and p27 were decreased. Calcium chloride, DFMO, piroxicam and sulindac administered for 7 days decreased the mitotic index and reduced the protein and mRNA levels of c-myc in colon tumors. Calcium chloride, DFMO and piroxicam increased the protein and mRNA levels of p16 and along with sulindac increased the protein level of p27, but not its mRNA. The other agents failed to modulate both the mitotic index and the expression of the genes. The ability of the chemopreventive agents to prevent colon tumors was determined. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane and 8 weeks later they were administered aspirin, 2-CPR, DFMO, piroxicam, 9-cis RA and rutin in their diet. The rats were killed 26 weeks after they started to receive the chemopreventive agents. The multiplicity of colon tumors was reduced by DFMO and piroxicam, increased by rutin and not affected by the other agents. Hence, agents that prevented colon cancer decreased the mitotic index and altered the expression of c-myc, p16 and p27 suggesting that modulation in the expression of these genes are potential biomarkers for chemopreventive activity.
Department of Pathology, HEB, Rm 202, Medical College of Ohio, 3055 Arlington Ave., Toledo, OH 43614-5806, USA. ltao@mco.edu
Lianhui
L
Tao
Paula M
PM
Kramer
Wei
W
Wang
Siming
S
Yang
Ronald A
RA
Lubet
Vernon E
VE
Steele
Michael A
MA
Pereira
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002122:Calcium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004195:Disease Models, Animal; D000518:Eflornithine / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D008940:Mitotic Index; D010894:Piroxicam / Q000494:pharmacology / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
D000970:Antineoplastic Agents; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D010894:Piroxicam; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002122:Calcium Chloride; D000518:Eflornithine