Personalized Medicine in Hereditary Cancer Syndromes
II-Jin Kim in Cancer Genetics and Genomics for Personalized Medicine, 2017
Similar to Lynch syndrome, targeted therapy development in FAP is mostly limited to NSAIDs, which exert antineoplastic effect through inhibition of Wnt-signaling pathway and by preventing accumulation of beta-catenin. Sulindac is one of the first NSAIDSs to show clinical activity in patients with FAP. In one of the initial randomized studies, treatment with sulindac led to significant decrease in number and size of patients with FAP [28]. Celecoxib is another NSAID with reported clinical activity in FAP patients. A randomized controlled trial patients with FAP who were treated with 400 mg BID celecoxib showed 28% reduction in the incidence of colorectal polyps compared to 4.5% reduction in patients treated with a placebo [29]. Aspirin, rectal sulindac, rectal indomethacin, sulindac sulfone, and rofecoxib also play preventative roles in FAP patients [17]. Tiracoxib, however, a selective COX-2 inhibitor, did not show any significant benefit [30].
Epidemiologic Linkage: Diet, Genetics, and Cancer
Maryce M. Jacobs in Vitamins and Minerals in the Prevention and Treatment of Cancer, 2018
Waddell et al.29 evaluated the effect of Sulindac, a non-steroid anti-inflammatory drug, on 7 patients with FAP (or the Gardner’s syndrome variant) following subtotal colectomy and ileoproctoscopy, and in 4 patients with intact colons. It was of extreme interest that all of the polyps were eliminated save for a few that arose in the rectal mucosa and the canal. While no cancers appeared in these patients on followup, given the temporal variability in colorectal cancer expression in this disease, one must use extreme caution in interpreting the role of Sulindac as protecting against cancer occurrence. We believe that the use of Sulindac should be subjected to careful clinical trials. Given the life-threatening aspect of FAP, we would not at this time employ the use of Sulindac in the place of prophylactic colectomy.
Benign Neoplasms of the Colon and Rectum
Philip H. Gordon, Santhat Nivatvongs, Lee E. Smith, Scott Thorn Barrows, Carla Gunn, Gregory Blew, David Ehlert, Craig Kiefer, Kim Martens in Neoplasms of the Colon, Rectum, and Anus, 2007
Winde et al. (229) conducted a prospective, controlled, nonrandomized Phase II dose-finding study from sulindac given rectally, and looked at the molecular mechanism by which sulindac worked. The study group (n = 28) and the control group (n = 10) underwent colectomy and IRA, with repeated proctoscopy with endoluminal ultrasound and biopsies every three months. The treatment group was given sulindac suppositories, 150 mg twice daily, for three months. Visible improvement was followed by a dose reduction to 50 mg daily. Worsening of the polyps required changing to the initial dose level. The results showed that all patients responded to sulindac after 24 weeks (at the latest). Complete reversion was reached with 50 mg/day in 78% of patients. Twenty-two percent had partial reversions of adenomas at latest re-examination and there was no influence on upper GI tract adenomas. There was a permanent antiproliferative effect (Ki-67) of low-dose sulindac, significant blocking of ras mutation activation, and a significant difference of untreated and treated mucosa in mutant p53 content. The follow-up was 4 years. The authors concluded that low dose antiproliferative sulindac therapy is highly effective in adenoma reversion in FAP patients. Sulindac shows influence on tumor-suppressor genes and on apoptosis markers. All cases with relapse represented by newly developed flat mucosal elevations respond to dose increases.
Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease
Published in Xenobiotica, 2020
Ian R. Phillips, Elizabeth A. Shephard
Sulindac, a nonsteroidal anti-inflammatory used for the treatment of familial adenomatous polyposis, is a prodrug. It is converted by gut bacteria from a sulfoxide to sulindac sulfide, the active form of the drug, which is then absorbed (Duggan et al., 1977; Etienne et al., 2003) and metabolized by FMO3 back to the inactive sulfoxide and, then, to sulindac sulfone (Hamman et al., 2000). In patients with familial adenomatous polyposis undergoing treatment with sulindac, the FMO3 variants c.472G>A[p.(Glu158Lys)] and c.923A>G[p.(Glu308Gly)] are associated with regression of existing polyps and protection against adenoma formation, particularly in those homozygous for the compound variant p.[(Glu158Lys);(Glu308Gly)] (Hisamuddin et al., 2004, 2005). Both variants decrease the ability of FMO3 to catalyze the oxygenation of sulindac in vitro (Hamman et al., 2000) and healthy individuals homozygous for p.[(Glu158Lys);(Glu308Gly)] metabolize the active drug more slowly than those homozygous for the ancestral allele (Tang et al., 2017). It is thought that reduction of FMO3 activity in vivo, as a consequence of these variants, would result in higher, more persistent concentrations of active drug, leading to increased drug efficacy and a positive effect on clinical outcome.
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
Forskolin is an AC activator that inhibits the growth of chemoresistant colon cancer cells. Low levels of forskolin combined with an inhibitor of the cAMP-selective PDE isotype 4 (PDE4) arrested growth of chemoresistant colon cancer cells. This action was thought to be mediated by cAMP levels elevated by the synergistic effect of a low-dose AC activator and PDE4 inhibitor [39]. Cilastozol, an oral anti-platelet drug that inhibits cAMP-selective PDE3, inhibits the motility and invasion of colorectal cancer cells by increasing cAMP levels [40]. Sulindac, a non-steroidal anti-inflammatory drug, has been studied in precancerous adenomas with promising results, but is not recommended for long-term use due to toxicities resulting from COX inhibition. However, evidence has suggested that sulindac’s anticancer activity is not through COX. Indeed, sulindac derivatives that were unable to bind COX, inhibited cGMP-degrading PDE5 and/or PDE10, activated cGMP/PKG signaling, and suppressed β-catenin to inhibit the growth of colon cancer cells [41].
Formyl peptide receptor-1 (FPR1) represses intestinal oncogenesis
Published in OncoImmunology, 2023
Julie Le Naour, Léa Montégut, Yuhong Pan, Sarah Adriana Scuderi, Pierre Cordier, Adrien Joseph, Allan Sauvat, Valerio Iebba, Juliette Paillet, Gladys Ferrere, Ludivine Brechard, Claire Mulot, Grégory Dubourg, Laurence Zitvogel, Jonathan G. Pol, Erika Vacchelli, Pierre-Laurent Puig, Guido Kroemer
Mice bearing the truncation mutation Min (multiple intestinal neoplasia) in codon 850 of the gene Apc (adenomatous polyposis coli), referred to as ApcMin/+ mice, show constitutive overactivation of the Wnt pathway leading to intestinal carcinogenesis.23,24 We treated such mice with the pharmacological Fpr1 antagonist cyclosporin H (CsH) once per week for 8 weeks (i.p. at 30 mg/kg/mouse), alone or in combination with two treatment periods of the non-steroidal anti-inflammatory drug sulindac (Figure 5a), which is known to attenuate intestinal oncogenesis.25 Of note, sulindac has a pleiotropic effect (on inflammation, proliferation, and Wnt/ß-catenin signaling).26–28 CsH treatment increased the number of lesions (atypical hyperplasias or intestinal adenomas across the intestine) developing in ApcMin/+ animals as compared to untreated ApcMin/+ mice. This pro-tumorigenic CsH effect was abrogated by simultaneous sulindac treatment (Figure 5b,c), suggesting that Fpr1 inhibition contributes to the manifestation of atypical hyperplasias or intestinal adenomas via pro-inflammatory effects.
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