ART2Dose: A comprehensive dose verification platform for online adaptive radiotherapy.

BACKGROUND: Online adaptive radiotherapy (ART) involves the development of adaptable treatment plans that consider patient anatomical data obtained right prior to treatment administration, facilitated by cone-beam computed tomography guided adaptive radiotherapy (CTgART) and magnetic resonance image-guided adaptive radiotherapy (MRgART). To ensure accuracy of these adaptive plans, it is crucial to conduct calculation-based checks and independent verification of volumetric dose distribution, as measurement-based checks are not practical within online workflows. However, the absence of comprehensive, efficient, and highly integrated commercial software for secondary dose verification can impede the time-sensitive nature of online ART procedures. PURPOSE: The main aim of this study is to introduce an efficient online quality assurance (QA) platform for online ART, and subsequently evaluate it on Ethos and Unity treatment delivery systems in our clinic. METHODS: To enhance efficiency and ensure compliance with safety standards in online ART, ART2Dose, a secondary dose verification software, has been developed and integrated into our online QA workflow. This implementation spans all online ART treatments at our institution. The ART2Dose infrastructure comprises four key components: an SQLite database, a dose calculation server, a report generator, and a web portal. Through this infrastructure, file transfer, dose calculation, report generation, and report approval/archival are seamlessly managed, minimizing the need for user input when exporting RT DICOM files and approving the generated QA report. ART2Dose was compared with Mobius3D in pre-clinical evaluations on secondary dose verification for 40 adaptive plans. Additionally, a retrospective investigation was conducted utilizing 1302 CTgART fractions from ten treatment sites and 1278 MRgART fractions from seven treatment sites to evaluate the practical accuracy and efficiency of ART2Dose in routine clinical use. RESULTS: With dedicated infrastructure and an integrated workflow, ART2Dose achieved gamma passing rates that were comparable to or higher than those of Mobius3D. Additionally, it significantly reduced the time required to complete pre-treatment checks by 3-4 min for each plan. In the retrospective analysis of clinical CTgART and MRgART fractions, ART2Dose demonstrated average gamma passing rates of 99.61 ± 0.83% and 97.75 ± 2.54%, respectively, using the 3%/2 mm criteria for region greater than 10% of prescription dose. The average calculation times for CTgART and MRgART were approximately 1 and 2 min, respectively. CONCLUSION: Overall, the streamlined implementation of ART2Dose notably enhances the online ART workflow, offering reliable and efficient online QA while reducing time pressure in the clinic and minimizing labor-intensive work.

Evaluation of fan-beam kilovoltage computed tomography image quality on a novel biological-guided radiotherapy platform.

Background and Purpose: A recently developed biology-guided radiotherapy platform, equipped with positron emission tomography (PET) and computed tomography (CT), provides both anatomical and functional image guidance for radiotherapy. This study aimed to characterize performance of the kilovoltage CT (kVCT) system on this platform using standard quality metrics measured on phantom and patient images, using CT simulator images as reference. Materials and Methods: Image quality metrics, including spatial resolution/modular transfer function (MTF), slice sensitivity profile (SSP), noise performance and image uniformity, contrast-noise ratio (CNR) and low-contrast resolution, geometric accuracy, and CT number (HU) accuracy, were evaluated on phantom images. Patient images were evaluated mainly qualitatively. Results: On phantom images the MTF10% is about 0.68 lp/mm for kVCT in PET/CT Linac. The SSP agreed with nominal slice thickness within 0.7 mm. The diameter of the smallest visible target (1% contrast) is about 5 mm using medium dose mode. The image uniformity is within 2.0 HU. The geometric accuracy tests passed within 0.5 mm. Relative to CT simulator images, the noise is generally higher and the CNR is lower in PET/CT Linac kVCT images. The CT number accuracy is comparable between the two systems with maximum deviation from the phantom manufacturer range within 25 HU. On patient images, higher spatial resolution and image noise are observed on PET/CT Linac kVCT images. Conclusions: Major image quality metrics of the PET/CT Linac kVCT were within vendor-recommended tolerances. Better spatial resolution but higher noise and better/comparable low contrast visibility were observed as compared to a CT simulator when images were acquired with clinical protocols.

Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats.

The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindac's antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of ß-catenin/Tcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMP/PKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy.

Machine characterization and central axis depth dose data of a superficial x-ray radiotherapy unit.

Objectives. The purpose of this study is to present data from the clinical commissioning of an Xstrahl 150 x-ray unit used for superficial radiotherapy,Methods. Commissioning tasks included vendor acceptance tests, timer reproducibility, linearity and end-effect measurements, half-value layer (HVL) measurements, inverse square law verification, head-leakage measurements, and beam output calibration. In addition, percent depth dose (PDD) curves were determined for different combinations of filter/kV settings and applicators. Automated PDD water phantom scans were performed utilizing four contemporary detectors: a microDiamond detector, a microSilicon detector, an EDGE detector, and a PinPoint ionization chamber. The measured PDD data were compared to the published values in BJR Supplement 25,Results. The x-ray unit's mechanical, safety, and radiation characteristics were within vendor-stated specifications. Across sixty commissioned x-ray beams, the PDDs determined in water using solid state detectors were in excellent agreement with the BJR 25 data. For the lower (<100 kVp) and medium-energy (≥100 kVp) superficial beams the average agreement was within [-3.6,+0.4]% and [-3.7,+1.4]% range, respectively. For the high-energy superficial (low-energy orthovoltage) x-rays at 150 kVp, the average difference for the largest 20 × 20 cm2collimator was (-0.7 ± 1.0)%,Conclusions. This study presents machine characterization data collected for clinical use of a superficial x-ray unit. Special focus was placed on utilizing contemporary detectors and techniques for the relative PDD measurements using a motorized water phantom. The results in this study confirm that the aggregate values published in the BJR 25 report still serve as a valid benchmark when comparing data from site-specific measurements, or the reference data for clinical utilization without such measurements,Advances in knowledge. This paper presents comprehensive data from the acceptance and commissioning of a modern kilovoltage superficial x-ray radiotherapy machine. Comparisons between the PDD data measured in this study using different detectors and BJR 25 data are highlighted.

Volumetric Modulated Arc Therapy Enabled Total Body Irradiation (VMAT-TBI): Six-year Clinical Experience and Treatment Outcomes.

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage >90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were <100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities.

Cancer incidence and mortality in the USA Astronaut Corps, 1959-2017.

OBJECTIVES: Cancer incidence and mortality are important outcomes in the surveillance of long-term astronaut health. We compare cancer incidence rates, cancer-specific mortality rates, and cancer case-fatality ratios in US astronauts with those in the US general population. METHODS: We use standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs) to index the incidence and mortality of various cancers against rates in the US general population, from the US astronaut cohort inception in April 1959 through 31 December 2017. We compare the lethality of these cancers using the relative case-fatality ratio. RESULTS: Overall cancer incidence and mortality were slightly lower than expected from national rates with SIR 82 (95% CI 63 to 104) and SMR 72 (95% CI 44 to 111) with a modest 14% reduction in case-fatality ratio. Prostate cancer and melanoma skin cancer had significant increases in incidence, with SIR of 162 (95% CI 109 to 232) and 252 (95% CI 126 to 452), respectively, though only melanoma had a significant increase in mortality, with SMR 508 (95% CI 105 to 1485). Lung cancer had a significant deficit of both cases and deaths, while colon cancer had sizeable (but not significant) reductions in incidence and mortality. CONCLUSIONS: The increase in incidence of melanoma is consistent with that observed in aircraft pilots, suggesting this may be associated with ultraviolet radiation or lifestyle factors rather than any astronaut-specific exposure. Reductions in lung cancer incidence and mortality, and trends towards such reductions in colon cancer, may be explained in part by healthy lifestyle, as well as differential screening among astronauts.

Surface guided motion management in glottic larynx stereotactic body radiation therapy.

BACKGROUND AND PURPOSE: Involuntary motion due to swallowing cause inaccurate dose delivery during larynx radiotherapy, a deviation that may be particularly problematic during stereotactic body radiation therapy (SBRT). The goal of this study was to develop a motion management solution for larynx SBRT using surface imaging. MATERIAL AND METHODS: Ten patients were recently treated on a phase II study of larynx SBRT on a LINAC equipped with a surface guidance system. A small region of the immobilization mask was manually cut open to allow surface tracking. Pre-treatment and intra-fractional CBCTs were acquired to verify internal anatomy. Patients were verbally instructed not to swallow during treatment. During treatment delivery, beam hold was initiated by the Motion Management Interface if surface motion exceeded a patient-specific threshold. Patient motion was recorded in log files and analyzed. We also performed phantom studies to assess the theoretical impact of gating on dose delivery. RESULTS: The frequency (6.5 ± 5.2 times per fraction) and duration (3.9 ± 2.5 seconds per swallow) of swallowing varied both between patients and fractions. The magnitude of each swallow showed mean peak amplitude at 5.8 ± 3.8 mm above baseline, mostly in the longitudinal direction. Beam duty cycle was 95.0% ± 7.0% (absolute range: 76-100%), with inefficiency most prominent in the early fractions. The 95th percentile residual motion was reduced from 3.4 mm to 2.3 mm with both verbal instruction and gating. Phantom studies confirmed dose delivery accuracy represented by gamma pass rate was improved by 5% using this approach. CONCLUSIONS: Laryngeal motion management using surface imaging is feasible and efficacious. Uncontrolled movement of the larynx was not uncommon during treatment, with gating reducing potential for unplanned dose deviations. Additional research is needed to determine the clinical benefit with this system.

Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library.

Disruptor of Telomeric Silencing 1-Like (DOT1L), the sole histone H3 lysine 79 (H3K79) methyltransferase, is required for leukemogenic transformation in a subset of leukemias bearing chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene, as well as other cancers. Thus, DOT1L is an attractive therapeutic target and discovery of small molecule inhibitors remain of high interest. Herein, we are presenting screening results for a unique focused library of 1200 nucleoside analogs originally produced under the aegis of the NIH Pilot Scale Library Program. The complete nucleoside set was screened virtually against DOT1L, resulting in 210 putative hits. In vitro screening of the virtual hits resulted in validation of 11 compounds as DOT1L inhibitors clustered into two distinct chemical classes, adenosine-based inhibitors and a new chemotype that lacks adenosine. Based on the developed DOT1L ligand binding model, a structure-based design strategy was applied and a second-generation of non-nucleoside DOT1L inhibitors was developed. Newly synthesized compound 25 was the most potent DOT1L inhibitor in the new series with an IC50 of 1.0 µM, showing 40-fold improvement in comparison with hit 9 and exhibiting reasonable on target effects in a DOT1L dependent murine cell line. These compounds represent novel chemical probes with a unique non-nucleoside scaffold that bind and compete with the SAM binding site of DOT1L, thus providing foundation for further medicinal chemistry efforts to develop more potent compounds.

Phylogeographic and phenotypic outcomes of brown anole colonization across the Caribbean provide insight into the beginning stages of an adaptive radiation.

Some of the most important insights into the ecological and evolutionary processes of diversification and speciation have come from studies of island adaptive radiations, yet relatively little research has examined how these radiations initiate. We suggest that Anolis sagrei is a candidate for understanding the origins of the Caribbean Anolis adaptive radiation and how a colonizing anole species begins to undergo allopatric diversification, phenotypic divergence and, potentially, speciation. We undertook a genomic and morphological analysis of representative populations across the entire native range of A. sagrei, finding that the species originated in the early Pliocene, with the deepest divergence occurring between western and eastern Cuba. Lineages from these two regions subsequently colonized the northern Caribbean. We find that at the broadest scale, populations colonizing areas with fewer closely related competitors tend to evolve larger body size and more lamellae on their toepads. This trend follows expectations for post-colonization divergence from progenitors and convergence in allopatry, whereby populations freed from competition with close relatives evolve towards common morphological and ecological optima. Taken together, our results show a complex history of ancient and recent Cuban diaspora with populations on competitor-poor islands evolving away from their ancestral Cuban populations regardless of their phylogenetic relationships, thus providing insight into the original diversification of colonist anoles at the beginning of the radiation. Our research also supplies an evolutionary framework for the many studies of this increasingly important species in ecological and evolutionary research.

Modeling Elekta VersaHD using the Varian Eclipse treatment planning system for photon beams: A single-institution experience.

The aim of this study was to report a single-institution experience and commissioning data for Elekta VersaHD linear accelerators (LINACs) for photon beams in the Eclipse treatment planning system (TPS). Two VersaHD LINACs equipped with 160-leaf collimators were commissioned. For each energy, the percent-depth-dose (PDD) curves, beam profiles, output factors, leaf transmission factors and dosimetric leaf gaps (DLGs) were acquired in accordance with the AAPM task group reports No. 45 and No. 106 and the vendor-supplied documents. The measured data were imported into Eclipse TPS to build a VersaHD beam model. The model was validated by creating treatment plans spanning over the full-spectrum of treatment sites and techniques used in our clinic. The quality assurance measurements were performed using MatriXX, ionization chamber, and radiochromic film. The DLG values were iteratively adjusted to optimize the agreement between planned and measured doses. Mobius, an independent LINAC logfile-based quality assurance tool, was also commissioned both for routine intensity-modulated radiation therapy (IMRT) QA and as a secondary check for the Eclipse VersaHD model. The Eclipse-generated VersaHD model was in excellent agreement with the measured PDD curves and beam profiles. The measured leaf transmission factors were less than 0.5% for all energies. The model validation study yielded absolute point dose agreement between ionization chamber measurements and Eclipse within ±4% for all cases. The comparison between Mobius and Eclipse, and between Mobius and ionization chamber measurements lead to absolute point dose agreement within ±5%. The corresponding 3D dose distributions evaluated with 3%global/2mm gamma criteria resulted in larger than 90% passing rates for all plans. The Eclipse TPS can model VersaHD LINACs with clinically acceptable accuracy. The model validation study and comparisons with Mobius demonstrated that the modeling of VersaHD in Eclipse necessitates further improvement to provide dosimetric accuracy on par with Varian LINACs.

Enhancing liver tumor localization accuracy by prior-knowledge-guided motion modeling and a biomechanical model.

BACKGROUND: Pre-treatment liver tumor localization remains a challenging task for radiation therapy, mostly due to the limited tumor contrast against normal liver tissues, and the respiration-induced liver tumor motion. Recently, we developed a biomechanical modeling-based, deformation-driven cone-beam CT estimation technique (Bio-CBCT), which achieved substantially improved accuracy on low-contrast liver tumor localization. However, the accuracy of Bio-CBCT is still affected by the limited tissue contrast around the caudal liver boundary, which reduces the accuracy of the boundary condition that is fed into the biomechanical modeling process. In this study, we developed a motion modeling and biomechanical modeling-guided CBCT estimation technique (MM-Bio-CBCT), to further improve the liver tumor localization accuracy by incorporating a motion model into the CBCT estimation process. METHODS: MM-Bio-CBCT estimates new CBCT images through deforming a prior high-quality CT or CBCT volume. The deformation vector field (DVF) is solved by iteratively matching the digitally-reconstructed-radiographs (DRRs) of the deformed prior image to the acquired 2D cone-beam projections. Using the same solved DVF, the liver tumor volume contoured on the prior image can be transferred onto the new CBCT image for automatic tumor localization. To maximize the accuracy of the solved DVF, MM-Bio-CBCT employs two strategies for additional DVF optimization: (I) prior-knowledge-guided liver boundary motion modeling with motion patterns extracted from a prior 4D imaging set like 4D-CTs/4D-CBCTs, to improve the liver boundary DVF accuracy; and (II) finite-element-analysis-based biomechanical modeling of the liver volume to improve the intra-liver DVF accuracy. We evaluated the accuracy of MM-Bio-CBCT on both the digital extended-cardiac-torso (XCAT) phantom images and real liver patient images. The liver tumor localization accuracy of MM-Bio-CBCT was evaluated and compared with that of the purely intensity-driven 2D-3D deformation technique, the 2D-3D deformation technique with motion modeling, and the Bio-CBCT technique. Metrics including the DICE coefficient and the center-of-mass-error (COME) were assessed for quantitative evaluation. RESULTS: Using limited-view 20 projections for CBCT estimation, the average (± SD) DICE coefficients between the estimated and the 'gold-standard' liver tumors of the XCAT study were 0.57±0.31, 0.78±0.26, 0.83±0.21, and 0.89±0.11 for 2D-3D deformation, 2D-3D deformation with motion modeling, Bio-CBCT and MM-Bio-CBCT techniques, respectively. Using 20 projections for estimation, the patient study yielded average DICE results of 0.63±0.21, 0.73±0.13 and 0.78±0.12, and 0.83±0.09, correspondingly. The MM-Bio-CBCT localized the liver tumor to an average COME of ~2 mm for both the XCAT and the liver patient studies. CONCLUSIONS: Compared to Bio-CBCT, MM-Bio-CBCT further improves the accuracy of liver tumor localization. MM-Bio-CBCT can potentially be used towards pre-treatment liver tumor localization and intra-treatment liver tumor location verification to achieve substantial radiotherapy margin reduction.

Contrapositive logic suggests space radiation not having a strong impact on mortality of US astronauts and Soviet and Russian cosmonauts.

Space travelers are exposed to unique forms of ionizing radiation that pose potentially serious health hazards. Prior analyses have attempted to quantify excess mortality risk for astronauts exposed to space radiation, but low statistical power has frustrated inferences. If exposure to deep space radiation were causally linked to deaths due to two particular causes, e.g., cancer and cardiovascular disease, then those cause-specific deaths would not be statistically independent. In this case, a Kaplan-Meier survival curve for a specific cause that treats deaths due to competing causes as uninformative censored events would result in biased estimates of survival probabilities. Here we look for evidence of a deleterious effect of historical exposure to space radiation by assessing whether or not there is evidence for such bias in Kaplan-Meier estimates of survival probabilities for cardiovascular disease and cancer. Evidence of such bias may implicate space radiation as a common causal link to these two disease processes. An absence of such evidence would be evidence that no such common causal link to radiation exposure during space travel exists. We found that survival estimates from the Kaplan-Meier curves were largely congruent with those of competing risk methods, suggesting that if ionizing radiation is impacting the risk of death due to cancer and cardiovascular disease, the effect is not dramatic.

Mortality of US astronauts: comparisons with professional athletes.

OBJECTIVE: Studies of mortality among US astronauts are complicated by the healthy worker effect, which predicts lower mortality for astronauts than the general population based solely on the ability to become and remain an astronaut. We attempt to evaluate astronaut mortality risk while accounting for the healthy worker effect. METHODS: We compare mortality rates of male US astronauts with those of professional athletes from Major League Baseball and the National Basketball Association between January 1, 1960 and May 31, 2018. RESULTS: Both athlete cohorts and astronauts had significantly lower-than-expected mortality in comparison with the general population. For the overall study period, there were no significant differences in all-cause mortality rates between astronauts and athletes. Astronauts were at greater risk of death from external causes (SMR=583; 95% CI 377 to 860) and reduced risk of death from cardiovascular disease (SMR=39; 95% CI 18 to 73) and all natural causes (SMR=67; 95% CI 47 to 93). CONCLUSIONS: The data presented here do not support increased mortality for astronauts due to unique exposures received in space. The mortality experience of astronauts as compared with professional baseball and basketball players should be re-examined periodically as part of the ongoing surveillance of astronaut mortality in years to come.

The effect of competing risks on astronaut and cosmonaut mortality.

Astronauts and cosmonauts have been reported to be at substantially lower age-specific risk of death from chronic disease (primarily heart disease and cancers) in comparison to the general populations of the United States and Russia, respectively. Yet, both groups have been at greater age-specific risk of death from external causes, mainly due to plane crashes and spacecraft accidents. In this study we tested the hypothesis that the reported reductions in mortality from natural causes result, to some degree, from survival bias created by early deaths from external causes. Statistical comparisons of baseline characteristics between cause-of-death groups showed no significant differences. Cause-specific survival curves showed no difference in long-term mortality from external causes among either astronauts or cosmonauts compared to Kaplan-Meier curves with censoring for competing causes. Cause-specific survival curves for natural causes suggested a possible upward bias in mortality estimates published thus far for both groups of space explorers. Differences in survival between Kaplan-Meier curves and the cause-specific survival curves were 7% and 5% for astronauts and cosmonauts respectively after 55 years. The data do not support the hypothesis that observed reductions in mortality from natural causes are due in whole or in part to bias created by deaths from external causes at young ages. The data imply that reports of cause-specific mortality for astronauts and cosmonauts may in fact systematically overestimate mortality rates, though these findings should be interpreted with caution as the data are thin at the extremes of follow-up time.

A small diversity library of α-methyl amide analogs of sulindac for probing anticancer structure-activity relationships.

Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer's disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.

Oxazole and thiazole analogs of sulindac for cancer prevention.

AIM: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. CONCLUSION: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.

Amine Containing Analogs of Sulindac for Cancer Prevention.

BACKGROUND: Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity. OBJECTIVE: Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities. METHOD: A series of sulindac amine analogs were designed and synthesized and then further modified in a "libraries from libraries" approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast). RESULTS: Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range. CONCLUSION: Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.

Synthesis and preliminary assessment of the anticancer and Wnt/ß-catenin inhibitory activity of small amide libraries of fenamates and profens.

As part of an ongoing program to study the anticancer activity of non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries of multiple NSAID scaffolds, we synthesized a series of NSAID amide derivatives and screened these sets against three cancer cell lines (prostate, colon and breast) and Wnt/ß-catenin signaling. The evaluated amide analog libraries show significant anticancer activity/cell proliferation inhibition, and specific members of the sets show inhibition of Wnt/ß-catenin signaling.

Diverse amide analogs of sulindac for cancer treatment and prevention.

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.