Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.More than 50,000 people in the United States will die in 2007 from colorectal cancer. In the United States, cancer is the leading cause of death in people under age 74 years (1), and colorectal cancer is the second most common cause of cancer deaths after lung cancer (2). Colorectal cancer may be prevented by removal of precursor adenomas found during screening sigmoidoscopy or colonoscopy (3), although rates are variable and range from 30% to 90% depending highly on reimbursement policies (4, 5).Diet and inflammation have been associated with risk of colorectal cancer (6), and a series of clinical trials have been conducted to test the efficacy of individual dietary supplements or anti-inflammatory agents to prevent the incidence or recurrence of colon polyps (7-14). Unfortunately, these trials have not translated into significant changes in medical practice for prevention or management of colon cancer for a variety of reasons, including lack of efficacy, unacceptable toxicities, and the availability of competing strategies for risk reduction (15).Studies in rodent models have shown that combination chemoprevention strategies are often more effective than those using individual agents (16,17). Difluoromethylornithine (DFMO) has been identified as a potent inhibitor of intestinal and colon carcinogenesis in animal models, especially in combination with nonsteroidal anti-inflammatory drugs (18)(19)(20). DFMO and the n...
Curcumin is derived from the spice tumeric and has anti-inflammatory and antineoplastic effects in vitro and in animal models, including preventing aberrant crypt foci (ACF) and adenomas in murine models of colorectal carcinogenesis. Inhibiting the production of the procarcinogenic eicosanoids prostaglandin E2 (PGE2) and 5-hydroxyeicosatetraenoic acid (5-HETE) can suppress carcinogenesis in rodents. Curcumin reduces mucosal concentrations of PGE2 (via inhibition of cyclooxygenases 1 and 2) and 5-HETE (via inhibition of 5-lipoxygenase) in rats. Although preclinical data support curcumin acitivity in many sites, the reported poor bioavailability of this agent supports its use in the colorectum We assessed the effects of oral curcumin (2 g or 4 g per day for 30 days) on PGE2 within ACF (primary endpoint), 5-HETE, ACF number, and proliferation in a non-randomized, open-label clinical trial in 44 eligible smokers with 8 or more ACF on screening colonoscopy. We assessed pre- and post-treatment concentrations of PGE2 and 5-HETE by liquid chromatography tandem mass spectroscopy in ACF and normal-tissue biopsies, ACF number via rectal endoscopy, proliferation by Ki-67 immunohistochemistry; and curcumin concentrations by high-performance liquid chromatography in serum and rectal mucosal samples. 41 Subjects completed the study. Neither dose of curcumin reduced PGE2 or 5-HETE within ACF or normal mucosa or Ki-67 in normal mucosa. A significant 40% reduction in ACF number occurred with the 4 g dose (P < 0.005); while ACF were not reduced in the 2 g group. This reduction was associated with a significant change in plasma curcumin/conjugate levels pre- and post-treatmeeng (5-fold increase; P = 0.009) in the 4 g group. Curcumin was well tolerated at both 2 g and 4g. Our data suggest that curcumin can decrease ACF number, and this is potentially mediated by curcumin conjugates delivered systemically.
Summary Neuroendocrine (NE) phenotype, seen in >30% of prostate adenocarcinomas (PCa), and NE prostate tumors are implicated in aggressive prostate cancer. Formation of NE prostate tumors in the TRAMP mouse model was suppressed in mice lacking the ubiquitin ligase Siah2, which regulates HIF-1α availability. Cooperation between HIF-1α and FoxA2, a transcription factor expressed in NE tissue, promotes recruitment of p300 to transactivate select HIF-regulated genes, Hes6, Sox9 and Jmjd1a. These HIF-regulated genes are highly expressed in metastatic PCa and required for hypoxia-mediated NE phenotype, metastasis in PCa and the formation of NE tumors. Tissue-specific expression of FoxA2 combined with Siah2-dependent HIF-1α availability enables a transcriptional program required for NE prostate tumor development and NE phenotype in PCa.
BACKGROUND. This study investigated the role of magnetic resonance imaging (MRI) in evaluation of pathologically complete response and residual tumors in patients who were receiving neoadjuvant chemotherapy (NAC) for both positive and negative HER‐2 breast cancer. METHODS. Fifty‐one individuals, comprised of 25 HER‐2 positive and 26 HER‐2 negative patients, were included in the study. Serial MRI studies were acquired before, during, and after NAC. On the basis of the final MRI, response was determined to be a clinically complete response ([CCR], no enhancement), probable CCR (residual enhancement equal to or less than that of glandular tissue), or residual tumor. All patients received surgery. Pathological outcomes were categorized as 1) no residual cancer, 2) no residual invasive cancer but ductal carcinoma in situ (DCIS) present, or 3) residual invasive cancer. The pathologically complete response (pCR) was defined as no invasive cancer. RESULTS. Complete clinical response as seen through MRI, including CCR and probable CCR, was identified in 35 (35 of 51, 69%) patients. MRI correctly diagnosed pCR in 26 (26 of 35, 74%) patients, including 18 of 19 (95%) patients in the HER‐2 positive group and 8 of 16 (50%) patients in the HER‐2 negative group (P < .005). The accuracy of MRI in identifying pCR varied according to the chemotherapy agent that was administered. MRI was more accurate in identifying pCR in patients who were receiving trastuzumab and less accurate in patients receiving bevacizumab. The high false‐negative rate found in HER‐2 negative patients was associated with residual disease that presented as scattered cells or small foci. In cases with residual bulk tumor, the lesion size, determined by MRI, correlated highly with that found in histopathological measurements (r = 0.93). CONCLUSIONS. MRI may predict pCR with high accuracy in HER‐2 positive patients, but it has a high false‐negative rate in HER‐2 negative patients, particularly in patients who are receiving antiangiogenic agents. Results indicate that the chemotherapy agent should be taken into consideration when using MRI to interpret therapeutic outcomes. More studies are needed to establish the role of MRI in managing, especially surgical planning, patients who are receiving NAC. Cancer 2008. © 2007 American Cancer Society.
The prospective multi-center ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a Diffuse Optical Spectroscopic Imaging (DOSI)-derived imaging endpoint, the Tissue Optical Index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine and delivered to 6 institutions where 60 subjects with newly-diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to 4 times during NAC treatment: baseline, one-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor to normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from −82% to 321%, with a median of −36%. Using pCR as the reference standard and receiver-operating characteristic curve methodology, %TOITN AUC was 0.60 (95% CI 0.39 to 0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI 0.63 to 1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction.
TBX3 is a transcription factor of the T-box gene family. Mutations in the TBX3 gene can cause hypoplastic or absent mammary glands. Previous studies have shown that TBX3 might be associated with breast cancer. Here, we show that TBX3 is overexpressed in malignant cells of primary breast cancer tissues by immunohistochemistry. TBX3 interacts with histone deacetylases (HDAC) 1, 2, 3, and 5. TBX3 interacts with HDAC1, 2, and 3 via two distinct binding sites. However, deletion of the repression domain (amino acids 566-624) of TBX3 completely abolishes its interaction with HDAC5. Endogenous TBX3 and HDACs interaction and colocalization are found in a breast cancer cell line by coimmunoprecipitation and immunofluorescence, respectively. The functional significance of the interaction between TBX3 and HDAC is also tested in a p14 ARF -luciferase reporter system. Results indicate that TBX3 represses expression of p14 ARF tumor suppressor and that a HDAC inhibitor is able to reverse the TBX3 repressive function in a dosage-dependant manner. This study suggests that TBX3 may function by recruiting HDACs to the T-box binding site in the promoter region. TBX3 repression to its targets is dependent on HDAC activity. TBX3 may serve as a biomarker for breast cancer and have significant applications in both breast cancer diagnosis and treatment. [Cancer Res 2008;68(3):693-9]
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