Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors.

Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the µ-opioid receptor (µ-OR). BMS-986187 is a structurally distinct PAM for the δ-opioid receptor (δ-OR) that has been reported to exhibit 100-fold selectivity in promoting δ-OR over µ-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the µ-OR and at the κ-opioid receptor (κ-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for δ-ORs and κ-ORs is approximately 20- to 30-fold higher than for µ-ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types (µ-OR, δ-OR, and κ-OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators.

Lack of healing reaction in the cancer wound.

Surgical wounds in cancer patients have a relatively high dehiscence rate. Although cancer resections are performed so as to include macroscopically non-involved tissues, some cancer cells can be present in the line of transection or surrounding tissues (R1 and R2 resections). The local healing process may facilitate proliferation of these localized cancer cells, and the high cytokine concentration within the healing wound may also attract cancer cells from distant sites to migrate into the wound area. The question arises how the tumor environment influences the wound healing process. The aim of the study was to monitor and compare, using immunohistochemical methods, the healing process of an incision wound performed through a metastatic liver tumor of colon cancer with the healing of a normal liver incision wound. The experiments were carried out on a CC531 colon cancer rat model. We observed impaired healing of cancer wounds at all stages of wound healing. Significantly fewer mononuclear cells infiltrated the cancer than the normal liver wounds. There were no significant differences in the phenotypes of infiltrating mononuclear cells. BrdU incorporation showed rapid proliferation of cancer but not infiltrating cells or fibroblasts in the cancer wounds. We observed no connective tissue formation and poor collagen deposition in cancer wounds. Additionally, cancer wounds were significantly deprived of newly formed vessels. We confirmed that the impaired migration and proliferation of inflammatory cells in cancer wounds and poor scar tissue formation contribute to impaired healing of cancer 'contaminated' wounds.

Role of base-excision repair in the treatment of childhood acute lymphoblastic leukaemia with 6-mercaptopurine and high doses of methotrexate.

Methotrexate (MTX) and 6-mercaptopurine (6MP) are the most commonly used drugs in the therapy of childhood acute lymphoblastic leukaemia (ALL). The main genotoxic effect of MTX resulting from inhibition of thymidylate synthase is mis-incorporation of uracil into DNA, which is considered essential for the effectiveness of the Protocol M in ALL IC BFM 2002/EURO LB 2002 regimens. In this study, we investigated the level of basal and induced DNA damage as well as the effectiveness of DNA repair in lymphocytes of children with ALL at four time-points during therapy with MTX and 6MP. To assess DNA damage and the efficacy of DNA repair we used the modified alkaline comet assay with uracil DNA glycosylase (Udg) and endonuclease III (EndoIII). In addition, we examined the induction of apoptosis in the lymphocytes of the patients during treatment. Finally, we compared the activity of base-excision repair (BER), involved in removal of both uracil and oxidized bases from DNA in lymphocytes of children with ALL and lymphocytes of healthy children. BER efficiency was estimated in an in vitro assay with cellular extracts and plasmid substrates of heteroduplex DNA with an AP-site. Our results indicate that there is a significant decrease in the efficacy of DNA repair associated with an increased level of uracil in DNA and induction of apoptosis during therapy. Moreover, it was found that the BER capacity was decreased in the lymphocytes of ALL patients in contrast to that in lymphocytes of healthy children. Thus, we suggest that an impairment of the BER pathway may play a role in the pathogenesis and therapy of childhood ALL.

The association of polymorphisms in DNA base excision repair genes XRCC1, OGG1 and MUTYH with the risk of childhood acute lymphoblastic leukemia.

The aim of this study was to evaluate the association of polymorphisms in genes encoding three key proteins of DNA base excision repair (BER): the OGG1 Ser326Cys, the MUTYH Tyr165Cys and the XRCC1 Arg399Gln with the risk of childhood acute lymphoblastic leukemia (ALL). Our study included 97 children patients with ALL (mean age 5.4±2.5) and 131 healthy children (mean age 6.2±2.8) used as controls. Genetic polymorphisms in BER pathway genes were examined using PCR and restriction fragment length polymorphism (RFLP). We have demonstrated that the OGG1 Cys/Cys genotype increases the risk of ALL (OR 5.36) whereas the Ser/Ser genotype variant strongly reduces the risk of this cancer among Polish children (OR 0.45). Although we did not observe the differences in single nucleotide polymorphisms (SNPs) in MUTYH and XRCC1 genes between control group and children with ALL, we have shown that the combined genotypes of examined genes can modulate the risk of childhood ALL in Polish population. We found that the combined genotype Arg/Gln-Cys/Cys of XRCC1/OGG1 (OR 3.83) as well as the Cys/Cys-Tyr/Tyr of OGG1/MUTYH (OR 6.75) increases the risk of ALL. In contrast, the combined genotype Arg/Arg-Ser/Ser of XRCC1/OGG1 (OR 0.40) as well as the Ser/Ser-Tyr/Tyr of OGG1/MUTYH (OR 0.43) played a protective role against this malignant disease. In conclusion, we suggest that polymorphisms of BER genes may be used as an important predictive factor for acute lymphoblastic leukemia in children.

Lack of functioning lymphatics and accumulation of tissue fluid/lymph in interstitial "lakes" in colon cancer tissue.

There is controversy as to whether intratumoral or peritumoral lymphatics play a dominant role in the metastatic process. The knowledge of how and where exactly tumor cells enter lymphatics is important for therapeutic targeting either the tumor core or peritumoral tissue with drugs or radiation. The basic questions remain: what is the morphological structure of intra- and peritumoral interstitium and lymphatics; what is their hydraulic conductivity?; and do these local physical conditions allow detached tumor cells to migrate to lymphatics? Identification of lymphatics has been based on immunohistochemical staining of lymphatic endothelial cells. This method does not, however, show the tissue fluid filled interstitial space and the shape of minute lymphatic vessels in tumors. We visualized the interstitial space and lymphatics in the central and peripheral regions of tumors using our original method of color stereoscopic lymphography in translucent tissue fragments and simultaneously with immunohistochemical staining of lymphatic and blood endothelial cells. The density of open and compressed lymphatic and blood vessels was measured in the intratumoral "hot spots" and at tumor edge. Moreover, the intratumoral tissue hydraulic conductivity was measured to define force necessary for propelling tissue fluid to peritumoral lymphatics. We found very few rudimentary minor blind lymphatics in the tumor core and numerous minor fluid "lakes" in the interstitium with no visible connection to the peritumoral lymphatics. Lining of "lakes" did not express molecular markers specific for lymphatic endothelial cells. Ninety-five percent of structures of what looked like lymphatics had compressed lumen and the hydraulic conductivity was 3 powers of magnitude lower than in the adjacent non-tumoral tissue. It can be concluded that lack of functioning lymphatics in tumor foci manifested by accumulation of tissue fluid in "lakes," low fluid conductivity and compression of lymphatics by tumor cells, and proliferating connective tissue may hamper escape of tumor cells. The most favorable site of entry of tumor cells to lymphatics seems to be the interface of the tumor and surrounding tissue with open lymphatics.

The δ-opioid receptor positive allosteric modulator BMS 986187 is a G-protein-biased allosteric agonist.

BACKGROUND AND PURPOSE: The δ-opioid receptor is an emerging target for the management of chronic pain and depression. Biased signalling, the preferential activation of one signalling pathway over another downstream of δ-receptors, may generate better therapeutic profiles. BMS 986187 is a positive allosteric modulator of δ-receptors. Here, we ask if BMS 986187 can directly activate the receptor from an allosteric site, without an orthosteric ligand, and if a signalling bias is generated. EXPERIMENTAL APPROACH: We used several clonal cell lines expressing δ-receptors, to assess effects of BMS 986187 on events downstream of δ-receptors by measuring G-protein activation, ß-arrestin 2 recruitment, receptor phosphorylation, loss of surface receptor expression, ERK1/ERK2 phosphorylation, and receptor desensitization. KEY RESULTS: BMS 986187 is a G protein biased allosteric agonist, relative to ß-arrestin 2 recruitment. Despite showing direct and potent G protein activation, BMS 986187 has a low potency to recruit ß-arrestin 2. This appears to reflect the inability of BMS 986187 to elicit any significant receptor phosphorylation, consistent with low receptor internalization and a slower onset of desensitization, compared with the full agonist SNC80. CONCLUSIONS AND IMPLICATIONS: This is the first evidence of biased agonism mediated through direct binding to an allosteric site on an opioid receptor, without a ligand at the orthosteric site. Our data suggest that agonists targeting δ-receptors, or indeed any GPCR, through allosteric sites may be a novel way to promote signalling bias and thereby potentially produce a more specific pharmacology than can be observed by activation via the orthosteric site.

Biased agonism: the quest for the analgesic holy grail.

Opioids alleviate pain, but adverse effects severely limit their usefulness. To solve this problem, biased ligands favoring 1 signaling pathway downstream of the µ-opioid receptor over another are being developed. In the target article, the authors synthesize compounds that preferentially activate G-protein or ß-arrestin signaling. They find that increased bias towards G-protein signaling produces better antinociception with minimal side effects in mice models. G-protein-biased opioids may provide a safer treatment strategy.

Comparison of the effects of arsenic and cadmium on benzo(a)pyrene-induced micronuclei in mouse bone-marrow.

This study was undertaken to investigate the genotoxic interactions between the common environmental pollutants: arsenic (As), cadmium (Cd) and benzo(a)pyrene (BaP), which are known to be human carcinogens. C57BL/6J/Han mice were pre-treated with 100mg cadmium chloride (Cd(2+))/L or 50mg sodium arsenite (As(3+))/L in drinking water for 7 days and then given a single dose of 200mg BaP/kg bw by intra-peritoneal injection. A third group of mice did not receive the pre-treatment and was given BaP alone. Mice were sacrificed before or at 12, 24, 48 or 72h after BaP administration. Chromosome damage in bone-marrow cells was assessed by use of the micronucleus test. The study revealed that BaP induced a statistically significant increase in micronucleus (MN) frequency at 48h after administration. In animals exposed to Cd in drinking water no enhancement of genotoxicity was observed compared with the control group that was given tap water only. In Cd/BaP co-exposed animals, the MN frequency at respective time points did not differ from that for the animals exposed solely to BaP. A statistically higher MN frequency was found in bone marrow of animals exposed to As compared with controls that received tap water (0.92+/-0.29% versus 0.38+/-0.13%, respectively). This effect was even more pronounced after combined exposure to As and BaP. In the co-exposed animals, significantly elevated levels of MN were detected in samples examined at 12, 24 and 48h after BaP administration, compared with animals receiving BaP alone (1.14+/-0.31%, 1.26+/-0.3% and 2.02+/-0.45% versus 0.44+/-0.13%, 0.44+/-0.11% and 1.04+/-0.44%, respectively). These findings imply strong interactions between As and BaP, but not between Cd and BaP, in inducing DNA damage in polychromatic erythrocytes in mouse bone-marrow.

Study on modelling of PMMA bone cement polymerisation.

This contribution is concerned with the modelling of PMMA-based bone cement polymerisation process and the associated heat effect. While existing models use description in terms of the so-called polymerisation fraction to fit the experimental data, the new model is constructed in such a way as to mimic the chemical processes taking place in the cement dough. The important phenomena are identified and the mathematical formulation is proposed.

Increased incidence of micronuclei assessed with the micronucleus assay and the fluorescence in situ hybridization (FISH) technique in peripheral blood lymphocytes of nurses exposed to nitrous oxide.

It has been postulated that exposure to nitrous oxide and halogenated anaesthetics is associated with various adverse health effects such as neurological and reproductive abnormalities or impairment of hepatic functions. In spite of the quite well known genotoxic effects of exposure to nitrous oxide in vivo, the mechanisms of these effects are still not clear. The aim of this study was to assess the frequency of micronuclei and to identify the type of chromosomal damage (clastogenic or aneugenic) in peripheral blood lymphocytes of operating-room nurses exposed to nitrous oxide. The study group comprised 46 women working at departments where the concentration of nitrous oxide ranged from 14 to 2308 mg/m3. The control population was composed of 28 women employed in the same hospitals but in non-surgical departments. The clastogenic/aneugenic effect of nitrous oxide was evaluated in lymphocytes using the standard micronucleus (MN) assay in combination with the fluorescence in situ hybridization (FISH) technique with pancentromeric probes. The results show a significant increase of the MN frequency in lymphocytes of exposed nurses compared with the control group (4.36+/-2.23 versus 9.02+/-4.67). The multiple regression analysis revealed a statistically significant relationship (p=0.0009) between MN frequency and exposure status, indicating that the level of exposure was the main factor affecting chromosomal damage. As assessed by FISH analysis, the overall frequencies of centromere-positive MN in the control and exposed groups were 43 and 49%, respectively. The increase observed in the exposed group may suggest a slight, statistically insignificant pro-aneugenic effect of exposure to nitrous oxide.

Band erosion: incidence, etiology, management and outcome after banded vertical gastric bypass.

BACKGROUND: Prosthetic devices have been used in bariatric operations to control the outlet of the gastric pouch and thus maintain weight loss. A complication of these prostheses is erosion or migration into the gastric lumen. The transected banded vertical gastric bypass (TBVGBP) is one of the modifications of gastric bypass. This modification has a silastic ring placed around the pouch to form the stoma. METHOD: The records of patients with band erosion (BE) after this operation were reviewed, to determine the incidence, etiology, management and outcome during a 9-year period. RESULTS: From May 1992 through May 2001, 2,949 primary and secondary TBVGBP were performed through the Center for Surgical Treatment of Obesity, utilizing 3 hospitals. 48 patients (1.63%) were documented to have BE: 40 documented by us and 8 by subsequent treating surgeons or at other facilities. Presenting symptoms were weight regain (18), stenosis or obstruction (17), pain (9), bleeding (7), and 5 were incidental findings. Some patients presented with more than one symptom. 8 were treated expectantly with spontaneous extrusion of the band. 16 bands have been removed endoscopically in 14 patients. 26 patients had open surgical revision, with 12 having band removal only and 14 band removal and revision of either the gastroenterostomy with or without band replacement or conversion to a distal Roux-en-Y gastric bypass (DRYGBP). Two patients who had revision to DRYGBP were re-revised to a longer common limb because of protein malnutrition. Three patients who had revision of the gastroenterostomy with band removal and replacement developed leaks that were managed non-surgically. Two of these re-eroded and the band was removed endoscopically with a subsequent revision to a DRYGBP. There was no death due to BE. CONCLUSION: BE is an uncommon complication of TBVGBP. Infection, previous bariatric operations and surgical technique play a role in BE. BE is best managed by endoscopic removal but can be treated expectantly or by open surgical intervention. Band removal without replacement or revision to DRYGBP may result in weight regain.

Panniculectomy adjuvant to obesity surgery.

BACKGROUND: Many patients who qualify for obesity surgery have a moderate to large panniculus (grade 1-5). They can benefit from panniculectomy done concurrently with gastric bypass (GBP) or subsequently after significant weight reduction, usually 18 months after the GBP. METHOD: Over the last 8 years, 2,231 bariatric operations were performed at the Center. 577 panniculectomies were done, with 428 (74.2%) concurrent with the GBP and 149 (25.8%) subsequent to the GBP. RESULTS: The redundant pannus weighed from 5 to 54.5 kg. Wound problems occured in 15.1% of panniculectomies. Transfusion was necessary in 1.9%. Hospital stay was 4 to 5 days, and was no greater than in patients that underwent the GBP alone. Those with grades 3-5 suffer more back-pain and problems of hygiene resulting from panniculitis. CONCLUSION: A very redundant panniculus compounds the patient's physical, social and emotional problems. Where cardiopulmonary and other medical status are satisfactory, a panniculectomy may be offered to patients with a symptomatic panniculus at the time of bariatric surgery, as a physically beneficial and cost-effective adjuvant.

Prospective comparative evaluation of stapled versus transected silastic ring gastric bypass: 6-year follow-up.

BACKGROUND: The effect of transecting vs. stapling the stomach in continuity in the banded gastric bypass (GBP) operation was studied. METHOD: 50 patients, 25 in each group, were enrolled into a prospective study to determine if transecting the stomach vs. stapling it in continuity in performing GBP for obesity decreases the incidence of gastro-gastric fistula formation without increased morbidity. RESULTS: The patient profiles in the 2 groups were very similar. The peri-operative complications included 1 splenic capsular injury in each group, controlled without a splenectomy. There was 1 anastomotic leak in the stapled and 1 bleeding from the cut edge of the bypassed stomach in the transected group, both requiring re-operations in the immediate postoperative period. There was no peri-operative mortality. The percent follow-up after 6 years was 80% and 88% in the stapled and transected groups respectively. The incidence of late complications of solid food intolerance, ventral incisional hernia, cholelithiasis and small bowel obstruction was similar in both groups. There were 8 gastro-gastric fistulas in the stapled group and 1 in the transected group. The reduction in body mass index and percent excess weight loss (66%) were similar in both groups. CONCLUSION: The incidence of gastro-gastric fistula may be reduced in GBP procedures by transecting the stomach as opposed to stapling it in continuity, without an increase in morbidity or mortality or any loss in the effectiveness of the operation.

Revision of failed gastric bypass to distal Roux-en-Y gastric bypass: a review of 65 cases.

BACKGROUND: No bariatric operation has been documented to effect adequate weight loss in all patients. Patients with inadequate weight loss or significant weight regain with an anatomically intact short-limb gastric bypass, of which the Fobi pouch operation (FPO) for obesity is a modification, are usually revised to a distal Roux-en-Y gastric bypass (DRYGBP) to enhance weight loss. METHOD: A retrospective review of the charts of all patients who had a revision to a DRYGBP at our Center during an 8-year period was carried out and the findings analyzed. RESULTS: 65 patients who had the FPO had a revision to the DRYGBP. Most were super obese patients who, even though they had lost significant weight, were still morbidly obese. Some were patients who had not lost adequate weight or <40% excess weight, and a small number were patients who requested more weight loss even though they had a BMI of < 35. 15 patients developed protein malnutrition requiring supplemental feeding. 6 required rerevision to short-limb gastric bypass. CONCLUSION: Revision of short-limb gastric bypass to DRYGBP usually enhances weight loss but at a cost of an increased incidence of protein malnutrition.

Thermal analysis of bone cement polymerisation at the cement-bone interface.

The two major problems that have been reported with the use of polymethylmethacrylate (PMMA) cement are thermal necrosis of surrounding bone due to the high heat generation during polymerisation and chemical necrosis due to unreacted monomer release. Computer models have been used to study the temperature and monomer distribution after cementation. In most of these models, however, polymerisation is modelled as temperature independent and cancellous bone is modelled as a continuum. Such models thus cannot account for the expected important role of the trabecular bone micro-structure. The aim of this study is to investigate the distribution of temperature and monomer leftover at the cancellous bone-cement interface during polymerisation for a realistic trabecular bone-cement micro-structure and realistic temperature-dependent polymerisation kinetics behaviour. A 3-D computer model of a piece of bovine cancellous bone that underwent pressurization with bone-cement was generated using a micro-computed tomography scanner. This geometry was used as the basis for a finite element model and a temperature-dependent problem for bone cement polymerisation kinetics was solved to simulate the bone cement polymerisation process in the vicinity of the interface. The transient temperature field throughout the interface was calculated, along with the polymerisation fraction distribution in the cement domain. The calculations revealed that the tips of the bone trabeculae that are embedded in the cement attain temperatures much higher than the average temperature of the bone volume. A small fraction of the bone (10%) is exposed to temperatures exceeding 70 degrees C, but the exposure time to these high temperatures is limited to 50s. In the region near the bone, the cement polymerisation fraction (about 84%) is less than that in the centre (where it is reaching values of over 96%). An important finding of this study thus is the fact that the bone tissue that is subjected to the highest temperatures is also subjected to high leftover monomer concentration. Furthermore the maximum bone temperature is reached relatively early, when monomer content in the neighbouring cement is still quite high.

[Sevofluran in pediatric practice--personal experience]. / Sevofluran w praktyce pediatrycznej--doswiadczenia wlasne.

Sevofluran a new inhalational anesthetic is a preferred anesthetic agent for induction and maintenance of pediatric anesthesia because of its rapid induction, recovery characteristics and acceptable cardiovascular profile--now also accessible in Poland. Sevofluran isn't an ideal anesthetic, and the issue of postoperative excitement, potential nephrotoxicity requires clarification. This study was designed to compare the emergence characteristics of sevoflurane with halotane anaesthesia in paediatric patients having various surgical intervention. 102 children divided for subgroup of premedicated and nonpremedicated, underwent inhalation induction with nitrous oxide/oxygen and sevofluran or halotane. Incremental doses of either study drug were added until loss of eyelash reflex was achieved. We didn't use higher concentrations of sevoflurane than 5.5 Vol% and 3.5 Vol% for halothane. Sevoflurane patients has a greater incidence of emergence agitation.

[Prevalence of malignant neoplasms in the Tarnów region in the years 1976-1992]. / Wystepowanie nowotworów zlosliwych w województwie tarnowskim w latach 1976-1992.

In the paper the prevalence and kinds of neoplasms in Tarnów region in the years 1976-1992 was presented. An increase in mortality, particularly in men, probably connected with the influence of carcinogenic environmental factors, especially smoking cigarettes, was observed. The most frequent malignant neoplasm in men was lung cancer whereas in women-breast cancer. An assessment of occurrence of malignant neoplasms in various part of Tarnów region was performed. In comparison with all Polish population as well as a majority of other regions' population, the Tarnów region is characterised by a little lower incidence of malignant neoplasms.

Dendrimers in therapy for breast and colorectal cancer.

Current trends in research dealing with methods of developing effective chemotherapy for the two most dangerous killers - breast and colon cancers have been discussed. The input brought by nanotechnology is presented with particular stress on the use of dendrimers. These unique "polymeric compounds" after modification can form intelligent species, transporting drugs into specific areas and at the same time can be used for monitoring the state of organs attacked by cancer cells, as well as the progress of the curing process. They can help to limit the anticancer drugs delivery to designed goals only, eliminating many side effects of chemotherapy. Breast and colon cancer are major problem for public health care in many countries all over the world. During last twenty years a dramatic increase in incidence of both of them has been observed, especially in industrialized countries. Probably, both of them are caused, apart from the hereditary syndromes, by specific point mutation, some hormonal factors in breast cancer and by the strong co-influence of environmental factors and dietary exposure of a patient.

Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines.

The purpose of the study was to characterize the involvement of reactive oxygen species (ROS) in mediating the cytotoxic effects of arsenic trioxide (ATO) in combination with sulindac or its metabolites: sulfide (SS) and sulfone (SF) on human leukemic cell lines. Jurkat, HL-60, K562, and HPB-ALL cells were exposed to the drugs alone or in combinations. Cell viability was measured using WST-1 or XTT reduction tests and ROS production by dichlorodihydrofluorescein diacetate staining (flow cytometry). Modulation of (a) intracellular glutathione (GSH) level was done by using L: -buthionine sulfoximine (BSO) or diethylmaleate (DEM), (b) NADPH oxidase by using diphenyleneiodonium (DPI), and (c) MAP kinases by using SB202190 (p38), SP600125 (JNK), and U0126 (ERK) inhibitors. ATO cytotoxicity (0.5 or 1 µM) was enhanced by sulindacs, with higher activity showed by the metabolites. Strong cytotoxic effects appeared at SS and SF concentrations starting from 50 µM. The induction of ROS production seemed not to be the major mechanism responsible for the cytotoxicity of the combinations. A strong potentiating effect of BSO on ATO cytotoxicity was demonstrated; DEM (10-300 µM) and DPI (0.0025-0.1 µM; 72 h) did not influence the effects of ATO. Some significant decreases in the viability of the cells exposed to ATO in the presence of MAPK inhibitors comparing with the cells exposed to ATO alone were observed; however, the effects likely resulted from a simple additive cytotoxicity of the drugs. The combinations of ATO with sulindacs offer potential therapeutic usefulness.