Colorectal tumor

Irinotecan (CPT-11) is approved for colorectal tumors. It is given by intravenous infusion. The most severe side effect is diarrhea, which can be severe and needs to be treated by a physician. Temporary liver dysfunction is generally asymptomatic. The other side effects are the same as those produced by topotecan. 

Since the uncontrolled proliferation is a peculiar characteristic of cancer cells, the proteins involved in DNA replication are attractive targets in modem chemotherapy. Several preclinical works showed in colorectal tumors, higher... 

Salonga, D., Danenberg, K. D., Johnson, M., et al. (2000) Colorectal tumors responding to 5-fluorouracil have low gene expression levels of drhydropyrimidine dehydrogenase, thymi-dylate synthase, and thymidine phosphorylase. Clin. Cancer Res. 6, 1322-1327. 

Aluminium hydroxide, which has been used widely as an antacid, also binds bile acids. However, there has been no clinical indication of altered CRC risk associated with its use and there was no observable difference in DMH-induced colorectal tumor incidence in rats receiving oral aluminium hydroxide compared with sham treatment. ... 

Pinheiro, N.A., Caballero, O.L., Soares, R, Reis, L.F.L., and Simpson, A.J.G., Significant overexpression of oligophrenin-1 in colorectal tumors detected by cDNA microarray analysis. Cancer Lett., 172, 67-73, 2001. 

Huber BE, Austin EA, Richards CA, et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene Significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 1994 91 8302-8306. 

Selective COX-2 inhibitors have also been shown to prevent early and late forms of colorectal neoplasia in rat models. Reddy et al. showed that administration of celecoxib inhibited aberrant colonic crypt foci (ACF) induction and multiplicity by about 40-49% in an azoxymethane-induced ACF rat model (81). Later the same investigators also showed that dietary administration of celecoxib can inhibit both the incidence and multiplicity of colon tumors by about 93 % and 97 %, respectively in the same rat model (82). Other researchers reported similar results with the Min mouse model (52). There is little data on human clinical trials with selective COX-2 inhibitors for colorectal tumor prevention. Recently Steinbach et al. conducted a double-blind, placebo-controlled study with 77 patients with FAP, and reported that treatment with celecoxib, a selective COX-2 inhibitor, for 6 mo led to a significant reduction (28%) in the number of colorectal polyps in these patients (50). Collectively, COX-2 nonspecific or specific NSAIDs appear to have chemopreventive activity against colorectal cancer development. Selective... 

COX-2 inhibitors may find aplace in colorectal tumor chemoprevention, since they seem to have a better gastrointestinal safety profile than other nonspecific NSAIDs when given to patients for a long time. In addition, this approach for colorectal tumors may be able to be expanded to other COX-2 expressing human tumors. 

Miyaki M, Konishi M, Kikuchi-Yanoshita R, et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 1994 54 3011-3020. 

Gann PH, Manson JE, Glynn RJ, et al. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 1993 85 1220-1224. 

L.G. Strauss, J.H. Clorius, P. Schlag, B. Lehner, B. Kimmig, R. Engenhart, M. Marin-Grez, F. Helus, F. Oberdorfer, P. Schmidlin, Recurrence of colorectal tumors PET evaluation. Radiology 170(2) (1989) 329-332. 

Sulindac is a racemic sulfoxide. Its deoxygenated metabolite (i.e., a sulfide) induces apoptosis, probably through inhibition of PPAR (Peroxisome Proliferator-Activated Receptor) It is probably the reason why suhndac seems to protect against colorectal cancers. Indeed, sulindac inhibits colorectal tumor cell growth. One other metabolite of sulindac, the sulfone exulind, is an inductor of apoptosis, and is currently in Phase III clinical trials for treatment of tumors (Figure 8.3). 

The TS gene is localized to the short arm of chromosome 18 at chromosome band 18p 11.32 (64). Chromosome 18 is generally known to be a site of frequent deletions in colorectal cancer tissues (64). Therefore it is highly probably that allelic imbalance occurs at the TS locus in some colorectal tumors. Zinzindohoue et al. were the first to report on the idea of LOH at the TS locus. The authors showed that the TS genotype from 2R/3R heterozygotes differed in ratio between 2R and the 3R bands. The observed LOH frequency at the TS locus was 63% (31 of 50) (65). 

Kralovanszky J, Koves 1, Orosz Z et al. Prognostic significance of the thymidylate biosynthetic enzymes in human colorectal tumors. Oncology 2002 62 167-174. 

Lenz H-J, Zhang W, Zahedy S et al. A 6 base-pair deletion in the 3 UTR of the thymidylate synthase (TS) gene prediets TS mRNA expression in colorectal tumors a possible eandidate gene for eoloreetal cancer risk. Proc Am Assoc Cancer Res (Abstract) 2002 43. 

Buckhaults P, Rago C, St Croix B, Romans KE, Saha S, Zhang L, Vogelstein B, Kinzler KW, Secreted and cell surface genes expressed in benign and malignant colorectal tumors, Cancer Res., 61 6996-7001, 2001. 

Canman CE, Tang HY, Normolle DP, Lawrence TS, Maybaum J. Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine Implications for mechanisms of resistance and cytotoxicity. Proc Natl Acad Sci USA 1992 89 10474-10478. 

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