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Purpose: To evaluate the changes in quality of life in noninfectious uveitis patients treated with 2 of the most commonly prescribed antimetabolite treatments., Design: Secondary analysis of a multicenter, block-randomized clinical trial., Methods: Eighty patients at Aravind Eye Hospitals in Madurai and Coimbatore, India, with noninfectious intermediate, posterior, or panuveitis were randomized to receive oral methotrexate, 25 mg weekly, or oral mycophenolate mofetil, 1 g twice daily, and were followed up monthly for 6 months. Best-corrected visual acuity, Indian Vision Function Questionnaire (IND-VFQ), and Medical Outcomes Study 36-item Short Form Survey (SF-36) were obtained at enrollment and at 6 months (or prior, in the event of early treatment failure)., Results: IND-VFQ scores, on average, increased by 9.2 points from trial enrollment to 6 months (95% confidence interval [CI]: 4.9, 13.5, P = .0001). Although the SF-36 physical component summary score did not significantly differ over the course of the trial, the mental component summary score decreased by 2.3 points (95% CI: -4.4, -0.1, P = .04) and the vitality subscale decreased by 3.5 points (95% CI: -5.6, -1.4, P = .001). Quality-of-life scores did not differ between treatment arms. Linear regression modeling showed a 3.2-point improvement in IND-VFQ score for every 5-letter improvement in visual acuity (95% CI: 1.9, 4.3; P < .001)., Conclusions: Although uveitis treatment was associated with increased vision and vision-related quality of life, patient-reported physical health did not change after 6 months of treatment, and mental health decreased. Despite improved visual outcomes, uveitis patients receiving systemic immunosuppressive therapy may experience a deterioration in mental health-related quality of life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive (19)F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

5-Fluorouracil (5-FU), a common chemotherapeutic agent used for the treatment of colorectal cancer (CRC), by itself has inadequate response rates; highlighting the need for novel and improved treatment regimens for these patients. Resveratrol, a naturally-occurring polyphenol, has been linked with chemosensitizing potential and anticancer properties; however, the underlying mechanisms for these effects remain poorly understood. The effect of resveratrol in parental CRC cell lines (HCT116, SW480) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R, SW480R) was examined by MTT assays, intercellular junction formation and apoptosis by electron- and immunoelectron microscopy, nuclear factor-kappaB (NF-κB) and NF-κB regulated gene products by western blot analysis in a 3D-alginate microenvironment. Resveratrol blocked the proliferation of all four CRC cell lines and synergized the invasion inhibitory effects of 5-FU. Interestingly, resveratrol induced a transition from 5-FU-induced formation of microvilli to a planar cell surface, which was concomitant with up-regulation of desmosomes, gap- and tight junctions (claudin-2) and adhesion molecules (E-cadherin) expression in HCT116 and HCT116R cells. Further, resveratrol significantly attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (decreased vimentin and slug, increased E-cadherin) and down-regulation of NF-κB activation and its translocation to the nucleus and abolished NF-κB-regulated gene end-products (MMP-9, caspase-3). Moreover, this suppression was mediated through inhibition of IκBα kinase and IκBα phosphorylation and degradation. Our results demonstrate that resveratrol can potentiate the anti-tumor effects of 5-FU on CRC cells by chemosensitizing them, inhibiting an EMT phenotype via up-regulation of intercellular junctions and by down-regulation of NF-κB pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To report the risk of endophthalmitis and other long-term complications in patients randomized to trabeculectomy in the Collaborative Initial Glaucoma Treatment Study., Design: A longitudinal cohort study using data collected from a multicenter, randomized clinical trial., Methods: Long-term postoperative complications in the 300 patients randomized to trabeculectomy in the Collaborative Initial Glaucoma Treatment Study were tabulated. Kaplan-Meier analyses were used to estimate the time-related probabilities of blebitis, hypotony, and endophthalmitis., Results: Two hundred eighty-five patients were included in the final trabeculectomy cohort after accounting for declining treatment assignment and other early events. Patients were followed up for an average of 7.2 years. One hundred sixty-three patients (57%) received 5-fluorouracil during surgery. Of the 247 patients with at least 5 years of follow-up, 50 required further treatment for glaucoma. Cataract extraction was performed in 57 patients (20%). Forty patients (14%) required bleb revision at least once. Bleb-related complications included bleb leak (n = 15), blebitis (n = 8), and hypotony (n = 4). Three patients were noted to have endophthalmitis, although the diagnosis in 2 patients was presumptive. The occurrences of blebitis, hypotony, or endophthalmitis were not significantly associated with 5-fluorouracil use. The Kaplan-Meier calculated risks of blebitis and hypotony at 5 years were both 1.5%, whereas the risk of endophthalmitis was 1.1%., Conclusions: The potential efficacy of trabeculectomy must be weighed against the long-term risk of complications, especially endophthalmitis, when selecting treatments for patients with open-angle glaucoma. We report a low 5-year risk of endophthalmitis (1.1%) and other bleb-related complications in the trabeculectomy cohort of the Collaborative Initial Glaucoma Treatment Study., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Filtration surgery is the standard invasive procedure for the management of intraocular pressure in advanced glaucoma. The key to a successful outcome is to modulate the normal wound healing cascade that leads to closure of the newly created aqueous outflow pathway. Antifibrotic agents such as mitomycin C and 5-fluorouracil have been increasingly used to modulate the wound healing process and increase surgical success. Although these agents have proven efficacy, they also increase the risk of complications. Efforts have centered on the identification of novel agents and techniques that can influence wound modulation without these complications. We detail new agents and methods under investigation to control wound healing after filtration surgery., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Metyrapone is a glucocorticoid synthesis inhibitor largely used to study glucocorticoid involvement in stress and memory processes. Metyrapone also acts as a stressor and therefore might modify sleep/wake patterns. However, its effects on rat sleep are unknown. We equipped 8 rats for telemetric assessment of EEG and EMG. They received first a saline injection and 2days later a 150mg/kg metyrapone injection. Metyrapone provoked immediately a waking effect together with a 3-h decrease in slow-wave sleep (SWS) and a 5-h decrease in rapid eye movement sleep (REM sleep). Thereafter, the rats exhibited homeostatic compensation through SWS and REM sleep rebounds recovering totally the sleep debt. The finding that metyrapone modified sleep patterns is important to consider for stress and memory studies using metyrapone., (2010 Elsevier B.V. All rights reserved.)

We have investigated whether long-term oral administration of the nucleoside reverse transcriptase inhibitor (NRTI) stavudine affects nociception in Sprague-Dawley rats, and whether any changes of nociception are accompanied by deterioration in activity and appetite. Stavudine (50 mg kg(-1)) was administered to rats orally once daily for six weeks in gelatine cubes. Mechanical hyperalgesia of the tail was assessed using a bar algometer, and thermal hyperalgesia by tail immersion in 49 degrees C water. Withdrawal latencies were compared to those of rats receiving placebo gelatine cubes. Withdrawal latencies to the noxious thermal challenge were not affected by stavudine, but those to the mechanical challenge were significantly decreased in rats receiving stavudine, compared to rats receiving placebo, from week three to week six of drug administration (P<0.05, ANCOVA with Newman Keuls post-hoc comparisons). The overall condition of the rats was assessed by recording daily voluntary wheel running distance and maximum running speed, food intake and body mass. Daily stavudine administration did not adversely affect voluntary running activity, appetite or growth. We have shown that long-term daily oral administration of the NRTI stavudine results in mechanical hyperalgesia in rats within three weeks without affecting appetite, growth and physical activity.

Purpose: The aim of this study is to determine if systemic absorption is present after 5-fluorouracil (5FU) is used in the vitrectomy infusion., Design: A two-case clinical study., Methods: A catabolite of 5FU, alpha-fluoro-beta-alanine (FBAL), was measured in urine samples of two patients who underwent vitrectomy using 5FU in the infusion fluid., Results: In both patients, FBAL was found in the urine samples collected up to 48 hours after the surgery, although in significantly different concentrations., Conclusions: The use of 5FU in the vitrectomy infusion fluid to prevent the formation of proliferative vitreoretinopathy may lead to significant general absorption and may be avoided in children and young adults.

Purpose: To compare the safety and efficacy of intraoperative 5-fluorouracil (5-FU) or Intraoperative mitomycin C (MMC) in eyes undergoing primary trabeculectomy., Design: Prospective double-masked randomized clinical trial., Methods: One hundred fifteen eyes of 103 patients with uncontrolled intraocular pressure (IOP) despite maximally tolerated medical therapy or laser were prospectively randomized in a double-masked fashion to one of two treatment groups in a single institution setting. Subject's eyes underwent primary trabeculectomy with either topical 5-FU (50 mg/ml for 5 minutes) or topical MMC (0.2 mg/ml for 2 minutes). Primary outcome measures included the number of eyes achieving target pressures of 21, 18, 15, and 12 mm Hg at 6 and 12 months postoperatively. Secondary outcome measures included IOP, best-corrected visual acuity, complications, and interventions., Results: Of the 115 eyes, 57 received 5-FU while 58 received MMC. A target IOP of 21 mm Hg at 6 months was achieved in 53 of 56 (95%) eyes in the 5-FU group and 54 of 57 (95%) eyes in the MMC group (P = 1.00). At 12 months, 45 of 48 (94%) eyes in the 5-FU group met a target IOP of 21 mm Hg while 48 of 54 (89%) eyes in the MMC group did (P =.49). The most common complications in each group were persistent choroidal effusions and bleb leak., Conclusion: Our study suggests that intraoperative topical 5-FU is at least as effective as intraoperative topical MMC in reducing IOP of eyes undergoing primary trabeculectomy.

Purpose: To estimate the prevalence and identify factors related to late-onset transconjunctival aqueous oozing and point leak from functioning blebs after trabeculectomy with 5-fluorouracil (5-FU) or mitomycin C., Design: Cross-sectional study., Setting: The study took place at the outpatient clinic of the Department of Ophthalmology, University of Tokyo Graduate School of Medicine (Tokyo, Japan). Four hundred three consecutive patients (403 eyes) with functional blebs at least 3 months after previously performed trabeculectomy were examined between December 1997 and February 1998. The Seidel test was performed with extended observation up to 15 seconds. Oozing was identified as transconjunctival aqueous egress without interruption of the conjunctival tissue or aqueous stream on the bleb wall. Logistic regression analyses of oozing and point leak in 331 eyes with an avascular area were performed using independent variables, including age, gender, glaucoma diagnosis, prior incisional surgery, antimetabolite use, combined cataract surgery, postoperative follow-up period, intraocular pressure (IOP), concurrent glaucoma therapy, bleb size, and avascular area size., Results: Of 403 eyes, 48 eyes (11.9%) had oozing and 8 eyes (2.0%) had point leak. Intraocular pressure was significantly lower and an avascular area was more frequent in eyes with oozing or leak than in eyes without (P <.001). Logistic regression analysis revealed that oozing was significantly more common after use of 5-FU than mitomycin C (P =.024), whereas point leak was associated with a larger avascular area (P =.045)., Conclusions: After trabeculectomy with antimetabolites, transconjunctival oozing is much more frequent than point leak. Oozing was significantly associated with the use of 5-FU and point leak with a larger avascular area in the bleb.

Drainage devices are routinely placed in the eyes of patients with glaucoma to reduce intraocular pressure (IOP) by providing controlled outflow of fluid (aqueous humor) via a filtering bleb. However, the natural wound healing response often interferes with fluid outflow by thickening the walls of the bleb over time, so that these devices rarely remain functional for more than 5 years. We investigated the use of controlled release of an antimetabolite, 5-fluorouracil (5-FU), within glaucoma drains to determine if the wound healing response could be reduced and the useful life span of the device increased. Collagen plugs containing 1.125 mg of 5-FU were placed in the silicone tubes of modified Baerveldt glaucoma drains. Eight drains with 5-FU and eight drains without 5-FU were implanted in one eye each of 16 New Zealand white rabbits: the contralateral eyes served as unoperated controls. Results were evaluated in terms of IOP, fibrous capsule thickness, macrophage density. and presence of type III collagen surrounding the drain plate, 3 and 6 months after implantation. In general, eyes implanted with antimetabolite-containing drains demonstrated significantly lower values for all evaluated parameters at 3 months and lower or equal values at 6 months, compared with the eyes not receiving 5-FU and the unoperated controls, indicating improved IOP-lowering function, reduced bleb wall thickness, and earlier achievement of a steady-state wound healing response. All eyes remained healthy throughout the 6-month duration of the study with no cytotoxicity complications in any of the eyes. Thus, biodegradable plugs placed within the silicone tubes of glaucoma drains can safely deliver 5-FU to filtering blebs over time, which could prolong the functional life of the bleb by decreasing the thickness of the anterior fibrous capsule and permitting sufficient fluid outflow to reduce IOP to physiological levels.

Purpose: To report a randomized clinical trial of postoperative subconjunctival injections of low-dose 5-fluorouracil in patients undergoing primary trabeculectomy., Methods: In a prospective, randomized clinical trial, 40 eyes of 40 patients were randomized to the low-dose 5-fluorouracil group and received three subconjunctival injections of 5 mg each over 11 postoperative days, and 40 eyes of 40 patients were randomized to trabeculectomy without 5-fluorouracil., Results: Mean (+/-SD) preoperative and 1-year postoperative intraocular pressures in the 5-fluorouracil group were 26.9 (+/-9.5) and 15.3 (+/-5.8) mm Hg, respectively. In the control group these were 25.9 (+/-8.1) mm Hg, and 15.8 (+/-5.1) mm Hg, respectively. The patients who received 5-fluorouracil had a mean reduction in intraocular pressure of 11.5 (+/-9.1) mm Hg at a median follow-up of 52.3 weeks. The control group had a mean reduction in intraocular pressure of 10.2 (+/-8.7) mm Hg at a median follow-up of 52.6 weeks. These differences were not statistically significant., Conclusions: Three postoperative subconjunctival 5-fluorouracil injections of 5 mg each after trabeculectomy in eyes at low risk for failure had no statistically or clinically significant effect on reduction of intraocular pressure with 1-year follow-up. Enhancement of success in this group of patients may require a larger total dose of 5-fluorouracil.

Purpose: To report outcomes and their association with preoperative and intraoperative factors of 456 combined cataract and glaucoma operations., Methods: A concurrent series (from January 1, 1987, to October 1, 1997) of one surgeon's consecutive 585 (456 patients) combined cataract extraction, intraocular lens implantation, and trabeculectomy surgeries, some with intraoperative mitomycin C and/or postoperative subconjunctival 5-fluorouracil. The study was a retrospective outcomes analysis for the first 191 operations (before June 10, 1992) and, subsequently, concurrent outcomes analysis for the latter 394 operations. Main outcome measures included postoperative visual acuity, intraocular pressure, number of glaucoma medications, intraoperative and postoperative adverse event rates, and reoperation for glaucoma or other ocular surgical or laser intervention., Results: Visual acuity was improved at the time of last follow-up in 402 (88.2%) of 456 first operated eyes of the 456 patients. Increasing age (coefficient = 0.025; CI [confidence interval], 0.017 to 0.33; P <.0001) was associated with a decreased likelihood of improved visual acuity, and a more recent operation (coefficient = 0.0037; 95% CI, -0.0064 to -0.0010, P =.0082) was associated with an increased likelihood of improved visual acuity. Forty-one (9.0%) of 456 eyes had reoperation to control intraocular pressure. Glaucoma reoperation was most strongly associated with a preoperative diagnosis other than primary open-angle, pigmentary, or pseudoexfoliative glaucoma, a history of previous ocular surgery, and high preoperative intraocular pressure. Mean intraocular pressure reduced 5.5 mm Hg from 21.8 mm Hg preoperatively to 16.3 mm Hg postoperatively and mean glaucoma medication from 2.0 to 0.9 medications. Mitomycin C or 5-fluorouracil use was significantly associated with a lower postoperative intraocular pressure and reduced postoperative glaucoma medication. Major postoperative adverse event or other reoperation (not for glaucoma) occurred in 12 (2.6%) of first operated eyes., Conclusions: Combined surgery outcomes in 456 first-operated eyes of 456 patients showed 88.2% improved visual acuity, 9% re-operation rate, 5.5 mm Hg mean intraocular pressure reduction, 1.1 glaucoma medication reduction, and a low major postoperative adverse event rate. Type of glaucoma, previous ocular surgery, and high preoperative intraocular pressure were the best predictors for the need for reoperation for glaucoma after combined surgery. Mitomycin C and/or 5-fluorouracil provided a greater reduction of mean intraocular pressure and glaucoma medication compared with patients not receiving these agents.

Interoreceptors in the central nervous system elicit compensatory behavioral and physiological responses to cellular glucopenia. Antagonism of mu and kappa opioid receptors attenuates glucoprivic hyperphagia, findings that implicate these peptidergic receptors in the central processing of metabolic regulatory signals. Several hypothalamic structures of critical importance for the regulation of energy balance exhibit one or both of these receptors. The following studies investigated the role of these opioid receptors in glucoprivic induction of immediate-early gene expression in these brain sites. Male rats were pretreated with beta-funaltrexamine (mu antagonist), Mr-1452 MS (kappa antagonist), or vehicle prior to intraperitoneal injection of the glucose antimetabolite, 2-deoxy-D-glucose (2DG), then sacrificed by transcardial perfusion 2 h later. Nuclear immunolabeling for the transcription factor, Fos, was observed in several preoptic and hypothalamic sites following 2DG administration. Rats pretreated with the mu antagonist exhibited significantly fewer Fos-positive neurons in the medial preoptic area and dorsomedial hypothalamic nucleus in response to 2DG, compared to vehicle-pretreated controls. Blockade of kappa receptors diminished 2DG and induced Fos staining in the paraventricular and supraoptic nuclei. Numbers of Fos-positive cells in the arcuate nucleus and ventrolateral hypothalamic area were not altered by either antagonist. The present data implicate mu and kappa opioid receptors in neural mechanisms underlying glucoprivic induction of the Fos stimulus-transcription pathway by local neurons in discrete hypothalamic sites.

The marsupial Sminthopsis crassicaudata increases food intake following a fast. However, the role of metabolic fuel availability, in particular glucose, in the regulation of food intake in this animal is unknown. In this study, we have demonstrated that neither insulin-induced hypoglycaemia nor metabolic blockade of glucose utilisation with 2-deoxy-D-glucose effects food intake compared to saline-treated controls, suggesting that mechanisms other than glucose availability are important in the regulation of food intake in this marsupial. These data are discussed in the context of the role of glucoprivation in feeding in other mammals.

We have investigated the possible benefits of elemental diets, especially a diet supplemented with L-glutamine, on maintenance of intestinal absorptive function in rat small intestine damaged by 5-fluorouracil. Although a standard rat diet sustained better body growth in control rats, each of the elemental diets and the diet containing intact casein in place of hydrolyzed casein was beneficial in promoting less body weight loss during the 3 d after 5-fluorouracil injection. The same significant benefit was seen in absorptive activity measured in small intestine in vitro 3 d after the cytotoxic injury. Glutamine supplementation, however, did not confer any significant advantages, although it did cause significant elevation of muscle glutamine pools. This elevation was substantially less than the corresponding increase in muscle glycine content after dietary supplementation with glycine.

Partial transections of the fiber connections between the temporal cortex and the lateral entorhinal cortex at a site of the white matter corresponding to the perirhinal cortex result in impaired visual memory accompanied by reduced concentrations of glutamate in both the temporal cortex and lateral entorhinal cortex. Intraperitoneal administration of the glycinergic receptor agonist D-cycloserine produces complete restoration of memory function, as measured by a brightness discrimination task in rats with temporal cortex/lateral entorhinal cortex transections. The purpose of the present study was to identify in which brain structures the compensatory activity might take place. The results show that infusion of cycloserine into either the temporal cortex or lateral entorhinal cortex fully ameliorated the impairment of temporal cortex/lateral entorhinal cortex lesions, whereas infusion into the hippocampal region caused only a mild improvement of the retention performance. Infusion of cycloserine into the frontal cortex or saline into the temporal cortex or lateral entorhinal cortex had no ameliorating effects on the memory dysfunction of rats bearing temporal cortex/lateral entorhinal cortex transections. It is concluded that the temporal cortex, lateral entorhinal cortex and perirhinal cortex are highly critical in forming visual memory.

Treatment of male Sprague-Dawley rats with buthionine sulfoximine (BSO), prior to administration of carbon-14(14C)-labelled 2-methylfuran (2MF) caused a marked decrease in the covalent binding of 14C-labelled 2MF metabolites to both DNA and protein, although there was no apparent change in the distribution of the labelled parent 2MF. BSO pretreatment also protected against hepatotoxicity of 2MF, as indicated by lower serum glutamic pyruvic transaminase (GPT) levels. Pretreatment with BSO offered protection only if administered 1.5 hr before 2MF dosage. Administration of 2MF, 4 and 6 hr after BSO resulted in manifestation of the hepatotoxicity of 2MF. Prior treatment with diethylmaleate (DEM), increased covalent binding of [14C]2MF to liver proteins and also elevated serum GPT levels. Thus, depletion of tissue glutathione (GSH) by two different chemicals acting by different mechanisms produced opposite effects on the covalent binding and toxicity of 2MF. Pretreatment with L-2-oxothiazolidine-4-carboxylate (OTZ), a promoter of GSH biosynthesis, increased the hepatic covalent binding of [14C]2MF and potentiated hepatotoxicity. However, administration of OTZ and BSO prior to an i.p. dose of 100 mg/kg of 2MF, decreased the hepatic covalent binding of [14C]2MF and decreased the hepatoxicity. The marked instability of the GSH conjugate of the reactive metabolite of 2MF may account for the potentiation of hepatotoxicity of 2MF by OTZ. A single s.c. dose of BSO, caused a transient increase in plasma cystine levels concurrent with the depletion of liver GSH. Administration of 2MF, 1.5 hr after BSO, significantly decreased plasma cystine levels as compared to control animals that received vehicle alone. Pretreatment with BSO also resulted in increased excretion of urinary metabolites in 2MF treated animals as compared to animals receiving 2MF alone. Thus, BSO probably protects against hepatoxicity of 2MF by indirectly causing more detoxification of the reactive metabolite of 2MF, as it does not alter the distribution of unmetabolized 2MF and does not have any apparent effect on the microsomal mixed-function oxidase which mediates the activation of 2MF. The enhanced detoxification of 2MF in BSO treated animals appears independent of the depleted GSH levels; it may result from increased availability of a better alternative nucleophile (i.e. cysteine), capable of conjugating with acetyl acrolein. Acetyl acrolein (AA) appears to be the principal reactive metabolite of 2MF which binds covalently to tissues. Previous in vitro studies have shown that cysteine is a better trapping agent of AA than GSH or N-acetyl-cysteine.

The effect of systemic glutathione (GSH) depletion on sensitization of bladder cancer cells to various antineoplastic agents was investigated using murine model, MBT-2. Subcutaneous injection(s) of buthionine sulfoximine (BSO) significantly depleted the GSH content in the tumor and organs. BSO pretreatment produced significant enhancement in the antitumor effect of cyclophosphamide (CY), though it failed to sensitize the tumors to doxorubicin hydrochloride (Adriamycin), cisplatin, mitomycin C, JM-8, methotrexate, vinblastine, and tumor necrosis factor. Mice tolerated cytotoxic agents alone and in combination with BSO except for cisplatin in combination with BSO. A 29 percent (4/14) mortality rate was observed in mice treated with BSO and divided schedule of cisplatin.