Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

BACKGROUND: MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan. METHODS: Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/day) IV for 5 days, for up to one year with G-CSF support. RESULTS: Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m2/day. CONCLUSION: High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].

Inhibition of polyamine biosynthesis preserves ß cell function in type 1 diabetes.

In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing ß cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with ß cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during ß cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve ß cell function in T1D through islet cell-autonomous effects.

GSTΠ stimulates caveolin-1-regulated polyamine uptake via actin remodeling.

Polyamines spermidine and spermine, and their diamine precursor putrescine, are essential for normal cellular functions in both pro- and eukaryotes. Cellular polyamine levels are regulated by biosynthesis, degradation and transport. Transport of dietary and luminal bacterial polyamines in gastrointestinal (GI) tissues plays a significant role in tissue polyamine homeostasis. We have reported that caveolin-1 play an inhibitory role in polyamine uptake in GI tissues. We investigated the mechanism of caveolin-1-regulated polyamine transport. We found that glutathione S-transferase Π(GSTΠ) was secreted from caveolin-1 knockdown cells and stimulated spermidine transport in human colon-derived HCT116 cells. GSTΠ secreted in the medium increased S-glutathionylated protein level in the plasma membrane fraction. Proteomic analysis revealed that actin was S-glutathionylated by GSTΠ. Immunofluorescence microscopy demonstrated that actin filaments around plasma membrane were S-glutathionylated in caveolin-1 knockdown cells. Inhibition of actin remodeling by jasplakinolide caused a decrease in polyamine uptake activity. These data support a model in which caveolin-1 negatively regulates polyamine uptake by inhibiting GSTΠ secretion, which stimulates actin remodeling and endocytosis.

Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer.

Cancer is a set of diseases characterized by uncontrolled cell growth. In certain cancers of the gastrointestinal tract, the adenomatous polyposis coli (APC) tumor suppressor gene is altered in either germline or somatic cells and causes formation of risk factors, such as benign colonic or intestinal neoplasia, which can progress to invasive cancer. APC is a key component of the WNT pathway, contributing to normal GI tract development, and APC alteration results in dysregulation of the pathway for production of polyamines, which are ubiquitous cations essential for cell growth. Studies with mice have identified nonsteroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, as potent inhibitors of colon carcinogenesis. Moreover, gene expression profiling has uncovered that NSAIDs activate polyamine catabolism and export. Several DFMO-NSAID combination strategies are effective and safe methods for reducing risk factors in clinical trials with patients having genetic or sporadic risk of colon cancer. These strategies affect cancer stem cells, inflammation, immune surveillance, and the microbiome. Pharmacotherapies consisting of drug combinations targeting the polyamine pathway provide a complementary approach to surgery and cytotoxic cancer treatments for treating patients with cancer risk factors. In this Minireview, we discuss the role of polyamines in colon cancer and highlight the mechanisms of select pharmacoprevention agents to delay or prevent carcinogenesis in humans.

Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model.

Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (sulindac-daily); (ii) for 2 weeks, then no sulindac for 2 weeks, cycle repeated 5 times (sulindac-2); (iii) for 10 weeks ("on"), then no sulindac for 10 weeks ("off"; sulindac-10); and (iv) no sulindac (sulindac-none). Sulindac-2 and sulindac-daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with sulindac-none (P < 0.0001). All of the treatment groups had statistically significantly lower final tumor burdens and slopes when compared with sulindac-none (P < 0.001). There was a prolonged latency period in the sulindac-10 group, with no significant difference between the "off" portion of this treatment and sulindac-none. These results suggest that, although daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall 4-week period (sulindac-2 model) can provide highly effective chemoprevention of colorectal cancer in this model. After cessation of sulindac treatment (sulindac-10 "off"), there is no evidence of either a persistent chemopreventive effect or a rebound effect. Cancer Prev Res; 10(8); 459-66. ©2017 AACR.

Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography.

Optical coherence tomography (OCT) is a high-resolution, nondestructive imaging modality that enables time-serial assessment of adenoma development in the mouse model of colorectal cancer. In this study, OCT was utilized to evaluate the effectiveness of interventions with the experimental antitumor agent α-difluoromethylornithine (DFMO) and a nonsteroidal anti-inflammatory drug sulindac during early [chemoprevention (CP)] and late stages [chemotherapy (CT)] of colon tumorigenesis. Biological endpoints for drug interventions included OCT-generated tumor number and tumor burden. Immunochistochemistry was used to evaluate biochemical endpoints [Ki-67, cleaved caspase-3, cyclooxygenase (COX)-2, ß-catenin]. K-Ras codon 12 mutations were studied with polymerase chain reaction-based technique. We demonstrated that OCT imaging significantly correlated with histological analysis of both tumor number and tumor burden for all experimental groups (P < 0.0001), but allows more accurate and full characterization of tumor number and burden growth rate because of its time-serial, nondestructive nature. DFMO alone or in combination with sulindac suppressed both the tumor number and tumor burden growth rate in the CP setting because of DFMO-mediated decrease in cell proliferation (Ki-67, P < 0.001) and K-RAS mutations frequency (P = 0.04). In the CT setting, sulindac alone and DFMO/sulindac combination were effective in reducing tumor number, but not tumor burden growth rate. A decrease in COX-2 staining in DFMO/sulindac CT groups (COX-2, P < 0.01) confirmed the treatment effect. Use of nondestructive OCT enabled repeated, quantitative evaluation of tumor number and burden, allowing changes in these parameters to be measured during CP and as a result of CT. In conclusion, OCT is a robust minimally invasive method for monitoring colorectal cancer disease and effectiveness of therapies in mouse models.

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. METHODS AND FINDINGS: Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). CONCLUSIONS: DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. TRIAL REGISTRATION: Clinicaltrials.gov NCT#01059071.

Combined benefit of prediction and treatment: a criterion for evaluating clinical prediction models.

Clinical treatment decisions rely on prognostic evaluation of a patient's future health outcomes. Thus, predictive models under different treatment options are key factors for making good decisions. While many criteria exist for judging the statistical quality of a prediction model, few are available to measure its clinical utility. As a consequence, we may find that the addition of a clinical covariate or biomarker improves the statistical quality of the model, but has little effect on its clinical usefulness. We focus on the setting where a treatment decision may reduce a patient's risk of a poor outcome, but also comes at a cost; this may be monetary, inconvenience, or the potential side effects. This setting is exemplified by cancer chemoprevention, or the use of statins to reduce the risk of cardiovascular disease. We propose a novel approach to assessing a prediction model using a formal decision analytic framework. We combine the predictive model's ability to discriminate good from poor outcome with the net benefit afforded by treatment. In this framework, reduced risk is balanced against the cost of treatment. The relative cost-benefit of treatment provides a useful index to assist patient decisions. This index also identifies the relevant clinical risk regions where predictive improvement is needed. Our approach is illustrated using data from a colorectal adenoma chemoprevention trial.

Dietary polyamine intake and polyamines measured in urine.

Dietary polyamines have recently been associated with increased risk of pre-malignant colorectal lesions. Because polyamines are synthesized in cells and taken up from dietary sources, development of a biomarker of exposure is challenging. Excess polyamines are primarily excreted in the urine. This pilot study seeks to identify dietary correlates of excreted urinary polyamines as putative biomarkers of exposure. Dietary polyamines/other nutrients were estimated from a food frequency questionnaire (FFQ) and correlated with urinary levels of acetylated polyamines in 36 men using 24-h urine samples. Polyamines, abundant in cheese and citrus, were highly positively correlated with urinary N(8)-acetylspermidine (correlation coefficient; r = 0.37, P = 0.03), but this correlation was attenuated after adjustment for total energy intake (r = 0.07, P = 0.68). Dietary energy intake itself was positively correlated with urinary total acetylated polyamine output (r = .40, P = 0.02). In energy-adjusted analyses, folic acid and folate from food were associated with urinary N(1),N(12)-diacetylspermine (r = 0.34, P = 0.05 and r = -0.39, P = 0.02, respectively). Red meat negatively correlated with total urinary acetylated polyamines (r = -0.42, P = 0.01). Our findings suggest that energy, folate, folic acid, saturated fat, and red meat intake, as opposed to FFQ-estimated dietary polyamines, are correlated with urinary polyamines.

Chemoprevention of prostate cancer with the polyamine synthesis inhibitor difluoromethylornithine.

In vitro and in vivo preclinical results suggest that inhibition of polyamine synthesis inhibits the progression of prostate cancer. These findings has led to two clinical trials in patients at risk for invasive prostate cancer with difluoromethylornithine which specifically and irreversibly inhibits ornithine decarboxylase which catalyses the conversion of ornithine to putrescine the rate limiting step in polyamines synthesis. We have conducted a phase IIa one month and placebo randomized phase IIb 12 months trials in patients at increased risk for invasive prostate cancer. Favorable reduction in prostate polyamine levels and prostate volume was documented with no difference in clinical hearing changes. Patients with Gleason's VI lesions in a surveillance cohort would be appropriate candidates for a definitive risk reduction trial although the unavailability of validated biomarkers for invasive progression would require a large and lengthy study.

Polyamines are oncometabolites that regulate the LIN28/let-7 pathway in colorectal cancer cells.

Polyamine metabolism is a highly coordinated process that is essential for normal development and neoplastic growth in mammals. Although polyamine metabolism is a validated pathway for prevention of carcinogenesis, the mechanisms by which polyamines elicit their tumorigenic effects are poorly understood. In this study, we investigated the role of polyamine metabolism in colon cancer by screening a non-coding RNA (ncRNA) platform to identify polyamine responsive signaling nodes. We report that multiple non-coding RNAs are altered by polyamine depletion including induction of microRNA (miRNA) let-7i, a member of the tumor suppressive let-7 family. The let-7 family targets several RNAs for translational repression, including the growth-associated transcription factor HMGA2 and is negatively regulated by the pluripotency factor LIN28. Depletion of polyamines using difluoromethylornithine (DFMO) or genetic knockdown of the polyamine-modified eukaryotic translation initiation factor 5A isoforms 1 and 2 (eIF5A1/2) resulted in robust reduction of both HMGA2 and LIN28. Locked nucleic acid (LNA) oligonucleotides targeting the seed region of the let-7 family rescued the expression of HMGA2, but not LIN28, in both DFMO-treated and eIF5A1/2 knockdown cultures. Our findings suggest that polyamines are oncometabolites that influence specific aspects of tumorigenesis by regulating pluripotency associated factors, such as LIN28, via an eIF5A-dependent but let-7-independent mechanism while the expression of proliferation-related genes regulated by let-7, such as HMGA2, is mediated through microRNA mediated repression. Therefore, manipulating polyamine metabolism may be a novel method of targeting the LIN28/let-7 pathway in specific disease states.

Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis.

Aggressive metastasis is the chief cause of the high morbidity and mortality associated with pancreatic cancer, yet the basis for its aggressive behavior remains elusive. Extracellular DNA (exDNA) is a recently discovered component of inflammatory tissue states. Here, we report that exDNA is present on the surface of pancreatic cancer cells where it is critical for driving metastatic behavior. exDNA was abundant on the surface and vicinity of cultured pancreatic cancer cells but absent from normal pancreas cells. Strikingly, treatment of cancer cell cultures with DNase I to degrade DNA nonspecifically reduced metastatic characters associated with matrix attachment, migration, and invasion. We further assessed the role of exDNA in pancreatic cancer metastasis in vivo using an orthotopic xenograft model established by implantation of pancreatic cancer cells expressing firefly luciferase. Noninvasive bioluminescent imaging confirmed that DNase I treatment was sufficient to suppress tumor metastasis. Mechanistic investigations suggested the existence of a positive feedback loop in which exDNA promotes expression of the inflammatory chemokine CXCL8, which leads to higher production of exDNA by pancreatic cancer cells, with a significant reduction in CXCL8 levels achieved by DNase I treatment. Taken together, our results strongly suggest that exDNA contributes to the highly invasive and metastatic character of pancreatic cancer.

Get the fat out!

Obesity is associated with increased risk of a number of cancers in humans, but the mechanism(s) responsible for these associations have not been established. It is estimated that 68% of adults are overweight or obese and that obesity may be causative in 4% to 7% of cancers in the United States. Several hypotheses have been put forward to explain the association between obesity and cancer including adipose-directed signaling (e.g., mTOR, AMPK), production of factors (e.g., insulin growth factor 1, fibroblast growth factor 1, and/or chronic inflammation associated with obesity. Huffman and colleagues used surgical methods to determine if visceral fat was causally related to intestinal tumorigenesis in the Apc(1638/N+) mouse in a manner independent of confounding factors such as caloric restriction. They found that caloric restriction could extend survival in both male and female Apc(1638/N+) mice but found that surgical removal of visceral fat was only effective in reducing macroadenomas in females. The results of this study do not identify the specific mechanism of association between visceral fat and intestinal carcinogenesis in female mice but do support the rationale for future cancer prevention trials that evaluate pharmacologic and behavioral strategies to reduce abdominal obesity in humans. Cancer Prev Res; 6(3); 161-4. ©2013 AACR.

Caveolin-1 is a novel regulator of K-RAS-dependent migration in colon carcinogenesis.

Caveolin-1 is an essential component of membrane caveolae. It is an important regulator of cellular processes such as signal transduction and endocytosis. We report here, for the first time, that caveolin-1 is a target of the K-RAS oncogene in colon carcinogenesis. Caveolin-1 is induced in colon cancer cells and in human colon tumor samples, in response to K-RAS activating mutations. An activated K-RAS oncogene transcriptionally induces caveolin-1 expression in human colon cancer cells and this effect is not restricted to the type of activating K-RAS mutation. Inhibition of the P-I3 Kinase-AKT pathway, but not the ERK MAPK pathway, both important K-RAS effectors, leads to a decrease in caveolin-1 expression indicating that the AKT pathway is involved in caveolin-1 expression in response to an activated K-RAS. Increased AKT signaling induces caveolin-1 expression by increasing the activity of the transcription factor, Sp1. Interestingly; caveolin-1 depletion alters K-RAS-dependent signaling by decreasing Grb2-SOS activity. Consistent with these finding, caveolin-1-depleted cells shows decreased migration in vitro. However, caveolin-1 overexpression by itself does not increase migration whereas an activated Src can increase migration in a caveolin-1-dependent manner. This increased migration is highly dependent on the RhoA GTPase, indicating that an activated K-RAS modulates migration in part via caveolin-1 induction, and increasing RhoA activity via phospho-caveolin-1. Our findings indicate that K-RAS regulates both caveolin-1 expression and other factors affecting caveolin-1 functions in colon cancer-derived cell migration.

Role of obesity in a randomized placebo-controlled trial of difluoromethylornithine (DFMO) + sulindac for the prevention of sporadic colorectal adenomas.

BACKGROUND: Chemoprevention with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) + sulindac markedly reduces risk of recurrent adenoma in colorectal adenoma patients. Obesity is associated with risk of colorectal adenoma and colorectal cancer. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO + sulindac versus placebo. METHODS: Our analysis included subjects enrolled in the phase III colorectal adenoma prevention clinical trial investigating DFMO + sulindac versus placebo. Patients were classified by obesity (body mass index, BMI ≥ 30 kg/m(2)) status at baseline. Pearson χ(2) statistic and Mann-Whitney U test were used to compare baseline characteristics, including rectal tissue polyamine levels. Log-binomial regression analysis was used to determine the risk ratio (RR) of recurrent adenomas, adjusted for covariates and an interaction term for obesity and treatment. RESULTS: The final analytic cohort was comprised of 267 patients. In separate regression models, the risk of adenoma recurrence after treatment compared to placebo was similar for obese (RR = 0.32, 95 % CI 15-71) and non-obese patients (RR = 0.27, 95 % CI 15-49). No significant interaction was detected between obesity, treatment, and risk of colorectal adenoma in the full regression model (p (interaction) = 0.91). CONCLUSIONS: Obesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO + sulindac versus placebo.

Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer.

To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors.

Dietary polyamine intake and risk of colorectal adenomatous polyps.

BACKGROUND: Putrescine, spermidine, and spermine are the polyamines required for human cell growth. The inhibition of ornithine decarboxylase (ODC), which is the rate-limiting enzyme of polyamine biosynthesis, decreases tumor growth and the development of colorectal adenomas. A database was developed to estimate dietary polyamine exposure and relate exposure to health outcomes. OBJECTIVE: We hypothesized that high polyamine intake would increase risk of colorectal adenoma and that the allelic variation at ODC G>A +316 would modify the association. DESIGN: Polyamine exposure was estimated in subjects pooled (n = 1164) from the control arms of 2 randomized trials for colorectal adenoma prevention [Wheat Bran Fiber low-fiber diet arm (n = 585) and Ursodeoxycholic Acid placebo arm (n = 579)] by using baseline food-frequency questionnaire data. All subjects had to have a diagnosis of colorectal adenoma to be eligible for the trial. RESULTS: A dietary intake of polyamines above the median amount in the study population was associated with 39% increased risk of colorectal adenoma at follow-up (adjusted OR: 1.39; 95% CI: 1.06, 1.83) in the pooled sample. In addition, younger participants (OR: 1.94; 95% CI: 1.23, 3.08), women (OR: 2.43; 95% CI: 1.48, 4.00), and ODC GG genotype carriers (OR: 1.59; 95% CI: 1.00, 2.53) had significantly increased odds of colorectal adenoma if they consumed above-median polyamine amounts. CONCLUSIONS: This study showed a role for dietary polyamines in colorectal adenoma risk. Corroboration of these findings would confirm a previously unrecognized, modifiable dietary risk factor for colorectal adenoma.

Chemoprevention in patients with genetic risk of colorectal cancers.

A number of genetic syndromes are known to convey a high risk of colorectal cancer. Current standards of medical practice for these patients involve genetic testing followed by screening and surgical procedures. Pharmaceutical therapies for any of these syndromes are limited in number and are generally not approved by any regulatory body for applications in these genetic groups. This review discusses advances in mechanistic understanding of the disease processes leading to the development of promising pharmaceutical therapies. Clinical trials of potential chemotherapeutic agents must focus on the reduction of disease-related events, including cancer and cancer-related mortality, in patients with genetic syndromes.

DFMO: targeted risk reduction therapy for colorectal neoplasia.

Strategies to decrease intracellular polyamine levels have been studied for their efficacy in reducing colorectal cancer (CRC) risk. A successful strategy combined agents that decreased polyamine synthesis by inhibiting ornithine decarboxylase with difluoromethylornithine (DFMO), and increased cellular export of polyamines by activating the spermidine/spermine acetyl transferase with non-steroidal anti-inflammatory drugs (NSAIDs). A Phase III trial treating resected adenoma patients with DFMO plus sulindac demonstrated marked reduction of metachronous adenomas, advanced adenomas and multiple adenomas compared to placebo. This combination regimen was well-tolerated, however there was a non-significant excess of cardiovascular events in the treatment arm compared to placebo as well as modest ototoxicity. Targeting this therapy to people at elevated risk of CRC, and employing clinical and genetic predictors, should improve patient benefit and reduce the risk of side effects to improve the acceptability of this strategy.

Defining the role of polyamines in colon carcinogenesis using mouse models.

Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM) models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min) mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.