Administration Of Mitomycin C Research Articles

Mitomycin C: new strategies to improve efficacy of a well-known therapy.

Mitomycin C (MMC) as an intravesical chemotherapeutic agent is a well-known option for treatment of nonmuscle invasive bladder cancer (NMIBC) recurrence; it is probably the most commonly used agent given its low rate of side effects and its efficacy.Both the American Urologic Association (AUA) and European Association of Urology (EAU) consider MMC as a standard treatment for immediate single-dose postoperative treatment and for adjuvant therapy in low and intermediate-risk NMIBC.Despite the popularity of this agent in the treatment of NMIBCs, many questions regarding the optimal approach to MMC therapy remain unanswered and the schedule widely used is empirical.Nevertheless, even when the current optimal approaches to MMC administration are used, a large proportion of NMIBCs recur.This apparent treatment resistance might be overcome by an optimization of standard MMC therapy or with a combination of MMC with other agents that have different mechanisms of action.Strategies to enhance passive delivery of MMC have been well studied and multiple measures are recommended for implementation of use in routine clinical practice.A modified scheme of instillation seems to be an easy and inexpensive alternative to increase efficacy of intravesical MMC and to also use this agent with an ablative intent.Enhancing tumor response with a sequential therapy is another option that has been investigated, mostly for chemo-immunotherapy wherein the different mechanisms of action of Bacillus of Calmette and Guerìn (BCG) and MMC are combined to achieve a higher response.

The effect of thermochemotherapy with mitomycin C on normal bladder urothelium, an experimental study.

To investigate the effects of thermochemotherapy with mitomycin C (MMC) on normal rabbit bladder urothelium and to compare it with standard intravesical MMC and hyperthermia with normal saline. Twenty-four male New Zealand rabbits, with a mean weight of 2.7 kg (in weight of 2.1–4.3 kg), were divided into three groups, each containing eight rabbits. Thermotherapy with only normal saline was performed in the first group, standard intravesical MMC was performed in the second group, and thermotherapy with MMC was performed in the last group. A week after the primary procedure, total cystectomy was performed and tissue samples were evaluated. The presence of epithelial vacuolar degeneration (p = 0.001), epithelial hyperplasia (p = 0.000), subepithelial fibrosis (p = 0.001) and hemorrhagic areas in the connective tissue (p = 0.002) was observed statistically significantly higher in the standard MMC group than in thermotherapy with normal saline group. There was almost a significant difference among standard MMC and normal saline group in terms of vascular congestion in the connective tissue (p = 0.08). Presence of epithelial vacuolar degeneration (p = 0.002), epithelial hyperplasia (p = 0.002), subepithelial fibrosis (p = 0.030), hemorrhagic areas (p = 0.011) and vascular congestion (p = 0.36) in the connective tissue was observed statistically significantly higher in the thermochemotherapy with MMC group than in standard intravesical MMC group. Polymorphonuclear cell infiltration was not considerable in any of the groups, and there was no significant difference between each groups (p = 0.140). Administration of intravesical MMC causes a toxic effect on the normal urothelium of the bladder rather than an inflammatory reaction. Heating MMC significantly increased this effect.

Mitomycin C-associated scleral stromalysis after pterygium surgery.

To describe complications after use of mitomycin C (MMC) as a surgical adjuvant in pterygium surgery. This is a retrospective chart review of patients presenting to a tertiary referral center over a 7-year period with a diagnosis of scleral stromalysis after previous pterygium removal. Sixteen eyes of 15 patients were identified with scleral stromalysis after pterygium surgery with the use of adjuvant MMC. Three eyes were excluded because of insufficient chart information or previous beta-irradiation treatment. Twelve of 13 eyes underwent surgical treatment for primary pterygium, and 1 eye was treated for recurrent pterygium. Time from initial pterygium surgery to presentation ranged from 1 month to 10 years. Dosage and routes of MMC administration included 0.02% intraoperative application to either the bare sclera or Tenon capsule with a range of 30 seconds to 3 minutes or topical administration 4 times daily for 2 weeks. In some cases, the dose and route of MMC administration were unknown. Four of 13 patients (31%) required a scleral patch graft with 1 patient (8%) requiring multiple patch grafts. Use of MMC in various forms and concentrations can cause devastating complications including scleral stromalysis. Scleral stromalysis may present anywhere from months to years after application. We suggest that MMC should be used with extreme caution when used as a surgical adjuvant for pterygium surgery. Patients must be urged to continue long-term follow-up after MMC use because of the potential for future anterior segment complications.

Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells.

The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

Mitomycin C guidelines: An improvement in department adherence through the process of audit, led by junior doctors

s / International Journal of Surgery 12 (2014) S13eS117 S104 0328: MITOMYCIN C GUIDELINES: AN IMPROVEMENT IN DEPARTMENT ADHERENCE THROUGH THE PROCESS OF AUDIT, LED BY JUNIOR DOCTORS Gerard Walls , David Curry, Hugh O'Kane. Regional Urology Unit, Belfast City Hospital, Northern Ireland, UK. Introduction: The authors intended to establish adherence to guidelines regarding time to administration of intravesical chemotherapy postTURBT, in the Regional Urology Unit. EORTC recommends Mitomycin C (MMC) instillation within 6 hours in eligible patients this reduces recurrence rates by 39%. Methods: Prospective audit of time to administration in all eligible patients during a 3 month period. Results were discussed at departmental level with a three tiered approach to improvement. Primarily, initiation of in-theatre instillation (Mostafid et al). Second, a training programme for ward staff in handling cytotoxic agents. Finally, awareness of the problem was raised to trainee urologists at the Regional Audit Meeting. A repeat three month audit series was performed six months later. The latter two processes had been implemented with plans for in-theatre administration on-going. Results: Initially, in 19 patients (40 eligible) the mean time to MMC administration was 18.3hrs (2.3-28.2hrs). 15.7% patients received MMC 3mm, first time. Unanimous, unequivocal histopathological diagnoses were achieved. Conclusions: Few biopsy devices provide satisfactory, representative and consistent samples for diagnosis. We experienced an unpredictable outcome with a 25% re-biopsy rate with various devices, however with BIGopsy forceps accurate histopathological diagnoses were achieved with a significant impact on the timely treatment for urothelial malignancies. 0401: HOW CLINICAL AUDIT HAS LED TO REDUCED RATES OF POST TRUS BIOPSY SEPSIS IN OUR TRUST Nicholas Gill , Michael Onyema, Anne Dyas, Vincent Koo, Paul Rajjayabun. Alexandra Hospital, Redditch, UK. Introduction: We recently reported the findings of a regional audit which identified rates of sepsis increasing to 1.8% following transrectal ultrasound guided prostate biopsies (TRUS). Following this audit I.V. Gentamicin 160mg was introduced as additional prophylaxis for patients undergoing TRUS biopsy. Our aim was to assess the impact of adding Gentamicin to the TRUS antibiotic prophylaxis bundle since implementation in August 2013. Methods: Analysis of all patients who underwent TRUS biopsy across our Trust between August-December 2013 with minimum 1-month follow up. Our findings were compared against our previous audit data and published literature. Results: Therewere 246 TRUS biopsy procedures carried out across the Trust following the introduction of our new antibiotic prophylaxis regime. Median age of the population examined was 67 years (range 42-84). Only 1 patient was admitted to Secondary care with significant sepsis (0.4%), 3 patients had positive urine cultures performed inPrimarycare but didnot require hospital admission (1.2%). There were no ITU admissions or mortalities. Conclusion: We conclude that the addition of I.V. Gentamicin has dramatically reduced the incidence of significant sepsis post-TRUS biopsy. This is an example of howwe have utilised audit tomodify clinical practice for the benefit of our patients. 0403: PROGNOSIS FOLLOWING PERCUTANEOUS NEPHROSTOMY INSERTION FOR MALIGNANT OBSTRUCTIVE UROPATHY: ONE CENTRE'S EXPERIENCE Nicholas Gill , Kevin Williams, Phil Holland, Chris Phillips, Fabio Conti, K. Wong, L. Delaney, L. Moore, Paul Rajjayabun. Alexandra Hospital,

MP11-13 PREDICTORS FOR THE USE OF INTRAVESICAL MITOMYCIN-C FOLLOWING TRANSURETHRAL RESECTION OF BLADDER TUMORS IN THE UNITED STATES: A POPULATION BASED ANALYSIS

You have accessJournal of UrologyGeneral & Epidemiological Trends & Socioeconomics: Practice Patterns, Cost Effectiveness II1 Apr 2014MP11-13 PREDICTORS FOR THE USE OF INTRAVESICAL MITOMYCIN-C FOLLOWING TRANSURETHRAL RESECTION OF BLADDER TUMORS IN THE UNITED STATES: A POPULATION BASED ANALYSIS Nedim Ruhotina, Jeffrey Leow, Wei Jiang, Benjamin L. Chung, Jonathan Rosenberg, Adam Kibel, Quoc Dien Trinh, and Steven L. Chang Nedim RuhotinaNedim Ruhotina More articles by this author , Jeffrey LeowJeffrey Leow More articles by this author , Wei JiangWei Jiang More articles by this author , Benjamin L. ChungBenjamin L. Chung More articles by this author , Jonathan RosenbergJonathan Rosenberg More articles by this author , Adam KibelAdam Kibel More articles by this author , Quoc Dien TrinhQuoc Dien Trinh More articles by this author , and Steven L. ChangSteven L. Chang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.428AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Multiple phase III trials have demonstrated that a single intravesical instillation of mitomycin C (MMC) within 24 hours after transurethral resection of non-muscle-invasive bladder tumor reduces the risk of locally recurrent disease. We analyzed a contemporary population-based cohort to determine the prevalence and predictors of immediate post operative administration of MMC (IPOMC) in the United States. METHODS We analyzed patient-level data from a proprietary national inpatient discharge database, which collects data from over 400 non-federal hospitals throughout the United States. We captured all men who underwent a transurethral resection of bladder tumor (TURBT) or cystoscopy with bladder biopsy between January 1, 2003, and December 31, 2010, based on the International Classification of Disease, 9th edition, codes 57.49 and 57.33 respectively. We identified the use of intravesical MMC within 24 hours of endoscopic therapy through a detailed review of the hospital charge data. The data were analyzed with descriptive statistics and logistic regression models. RESULTS Overall, the rate of IPOMC utilization increased from 4.0% in 2003 to 10.0% in 2010. While in providers who administered IPOMC at least once, the rate of IPOMC use increased from 14.6% in 2003 to 25.4% in 2010. There was a higher likelihood of IPOMC use in patients who were older than age 75 compared to patients less than age 55 (OR 1.73, p=0.03). Patients who had a Charlson co-morbidity index (CCI) of 1 were less likely to receive IPOMC compared to patients with CCI of 0 (OR 0.81, p=0.01). In subgroup analysis of providers who administered at least one dose of IPOMC, the highest annual volume providers were less likely to administer IPOMC (OR 0.54, p=0.01) than lower volume providers. Compared to lowest volume hospitals, in the highest volume hospitals there was a lower likelihood of IPOMC administration (OR 0.6, p=0.04). Patient gender, race, insurance status, hospital location, size and teaching affiliation did not affect IPOMC administration. CONCLUSIONS Despite the abundance of data supporting the use of intravesical MMC within 24 hours after endoscopic management of bladder tumors, adoption of this practice in the United States is severely limited. Our findings are particularly concerning as young patients who would most likely benefit from IPOMC are the ones least likely to receive the therapy. Barriers to more widespread use may include surgeon experience and biases and institutional restrictions. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e100-e101 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Nedim Ruhotina More articles by this author Jeffrey Leow More articles by this author Wei Jiang More articles by this author Benjamin L. Chung More articles by this author Jonathan Rosenberg More articles by this author Adam Kibel More articles by this author Quoc Dien Trinh More articles by this author Steven L. Chang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Optimizing intravesical mitomycin C therapy in non-muscle-invasive bladder cancer

Nearly three-quarters of all newly diagnosed urothelial cancers are non-muscle-invasive bladder cancers (NMIBCs). Although bladder-preserving surgery can be used to treat NMIBC, the rate of recurrence remains high. Intravesical chemotherapy has been shown to reduce the rate of NMIBC recurrence, and mitomycin C (MMC) has become the most commonly used intravesical cytotoxic agent. Despite the popularity of this agent in the treatment of NMIBCs, many questions regarding the optimal approach to MMC therapy remain unanswered. Strategies to enhance delivery of MMC have been well studied and multiple measures are recommended for implementation in routine clinical practice. In addition, less widely investigated techniques, such as hyperthermia and electromotive drug administration, have been shown to increase the efficacy of MMC therapy. Nevertheless, even when the current 'optimal' approaches to MMC administration are used, a large proportion of NMIBCs recur. This apparent treatment resistance might be overcome by combination of MMC with other agents that have different mechanisms of action and are unlikely to have cross-resistance. Study of the mechanisms of resistance is, therefore, important to identify key pathways underlying this phenomenon, which could be rationally targeted using specific combinations of drugs. Knowledge of these mechanisms might also reveal markers of responsiveness to therapy that could be used for patient selection.

Enhanced efficacy of postoperative adjuvant chemotherapy in advanced gastric cancer: results from a phase 3 randomized trial (AMC0101)

To improve the efficacy of adjuvant chemotherapy with mitomycin-C and fluoropyrimidine (Mf) in gastric cancer, we designed a new regimen (iceMFP) and investigated in a phase III study. We randomly assigned 640 patients with resectable and macroscopically recognizable serosa-invading gastric cancer to Mf or iceMFP group during operation. The Mf consisted of intravenous mitomycin-C (20 mg/m(2)) at 3-6 weeks after surgery and oral doxifluridine (460-600 mg/m(2)/day) starting 4 weeks after the administration of mitomycin-C and continuing for 3 months. The iceMFP consisted of intraoperative intraperitoneal cisplatin (100 mg), intravenous mitomycin-C (15 mg/m(2)) on postoperative day 1, followed by oral doxifluridine for 12 months, and six monthly intravenous cisplatin (60 mg/m(2)). The primary endpoint was 3-year recurrence-free survival (RFS). A total of 521 patients (258 in Mf, 263 in iceMFP) were eligible for analysis after excluding patients with stage I disease, distant metastasis, or R1 resection. With a median follow-up of 3.5 years, the iceMFP group had a higher RFS (hazard ratio [HR] 0.70; 95 % confidence interval [CI] 0.54-0.90; p = 0.006; 3-year RFS 60 % vs. 50 %) and overall survival (HR 0.71; 95 % CI 0.53-0.95; p = 0.02; 3-year overall survival, 71 vs. 60 %) compared with the Mf group. This was confirmed at extension analysis after a median 6.6 years of follow-up. Both regimens were well tolerated with no differences in surgical complications. The efficacy of adjuvant Mf was significantly improved by the additional therapeutic strategies of iceMFP. Considering negative results of AMC0201, these suggest that early initiation of chemotherapy and/or intraperitoneal cisplatin played a distinct role in the improved efficacy.

Prediction of Intravesical Recurrence After Radical Nephroureterectomy: Development of a Clinical Decision-making Tool

BackgroundIntravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. ObjectiveThe aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. Design, setting, and participantsWe performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. InterventionsRNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). Outcome measurements and statistical analysesUnivariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. Results and limitationsWith a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85%±1%, 78%±1%, 68%±1%, and 47%±2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values ≤0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study. ConclusionsIntravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU.

1783 LONG-TERM OUTCOMES OF ELECTRO-MOTIVE DRUG ADMINISTRATION OF MITOMYCIN-C AFTER FAILED INTRAVESICAL BCG IMMUNOTHERAPY IN HIGH RISK, NON-MUSCLE INVASIVE TRANSITIONAL CELL CARCINOMA OF THE BLADDER

You have accessJournal of UrologyBladder Cancer: Superficial (II)1 Apr 20131783 LONG-TERM OUTCOMES OF ELECTRO-MOTIVE DRUG ADMINISTRATION OF MITOMYCIN-C AFTER FAILED INTRAVESICAL BCG IMMUNOTHERAPY IN HIGH RISK, NON-MUSCLE INVASIVE TRANSITIONAL CELL CARCINOMA OF THE BLADDER Ruairidh Crawford, Hannah Wright, Jonathan Borwell, Theresa Parker, Bruce Montgomery, and Neil Barber Ruairidh CrawfordRuairidh Crawford Frimley, United Kingdom More articles by this author , Hannah WrightHannah Wright Frimley, United Kingdom More articles by this author , Jonathan BorwellJonathan Borwell Frimley, United Kingdom More articles by this author , Theresa ParkerTheresa Parker Frimley, United Kingdom More articles by this author , Bruce MontgomeryBruce Montgomery Frimley, United Kingdom More articles by this author , and Neil BarberNeil Barber Frimley, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2873AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A recent global shortage of Bacillus Calmette-Guérin (BCG) has forced urologists to consider alternative strategies for treatment of non-muscle invasive bladder cancer (NMIBC). Electro-motive drug administration of Mitomycin-C (EMDA MMC) is one possible alternative but there is little long-term data available. We look at the efficacy and tolerability of EMDA MMC in a select patient group. METHODS Retrospective analysis of patients at a single institution who had received intravesical EMDA MMC since 2006. Indications for this treatment included recurrence or persistence of disease following initial treatment with intravesical BCG or failure to tolerate that treatment for high-risk NMIBC. All patients were considered unacceptably high risk for radical cystectomy. Clinical and operative notes and histology were analyzed to determine tolerability, rates of recurrence and disease progression. RESULTS 26 patients were identified; 20 of these completed the treatment fully. The remaining 6 either did not tolerate treatment or followed up at a different hospital. The average age at time of treatment was 79. There were 21 males and 5 females. With a mean follow-up of 44 months, 14 patients (70%) were found to have disease recurrence within the first 12 months. All were subsequently managed endoscopically. The mean time to disease recurrence was 8.4 months. Disease progression was seen in only 2 patients; one developed new high grade NMIBC and another developed metastatic disease 41 months following treatment. There were no other cases of disease progression. Only 4 patients (15.4%) discontinued their treatment due to skin reactions, intolerable storage type lower urinary tract symptoms or significant haematuria. No patients had systemic reactions to the treatment. CONCLUSIONS EMDA MMC may have an important role in treating patients who have failed BCG therapy for high risk NMIBC and who are too unfit for radical surgery. A 30% complete response rate at a year, with an apparent low risk of progression suggests impressive disease control in the long-term in this poor prognostic group. Tolerability is similar to BCG and of note, there were no systemic reactions. More formal evaluation in the form of a well powered, randomized and probably multi-centred study is needed to fully evaluate the role of EMDA MMC in the treatment of high risk NMIBC, either as an initial treatment or as salvage after BCG, and certainly suggests a potential role whilst BCG availability worldwide remains a problem. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e733 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ruairidh Crawford Frimley, United Kingdom More articles by this author Hannah Wright Frimley, United Kingdom More articles by this author Jonathan Borwell Frimley, United Kingdom More articles by this author Theresa Parker Frimley, United Kingdom More articles by this author Bruce Montgomery Frimley, United Kingdom More articles by this author Neil Barber Frimley, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

One Versus 2 Cycles of Mitomycin C in Concurrent Chemoradiation for Treatment of Anal Canal Carcinoma: An Analysis of Outcomes and Toxicity

Concurrent chemoradiation (CRT) with fluorouracil (5-FU) and mitomycin C (MMC) is widely accepted as the preferred definitive treatment in anal canal carcinoma (ACC). The current treatment protocol in Alberta has been administration of MMC followed by infusional 5-FU during weeks 1 and 5 of radiation. Administration of the second bolus of MMC, however, has been based largely on center preference. Given limited published data comparing outcomes for various MMC regimens, our objective was to compare efficacy and toxicity of 1 vs 2 cycles of MMC in ACC treatment.

Curcumin enhanced antiproliferative effect of mitomycin C in human breast cancer MCF-7 cells in vitro and in vivo

To investigate the efficacy of mitomycin C (MMC) in combination with curcumin in suppressing human breast cancer in vitro and in vivo. Human breast cancer MCF-7 cells were used. Cell viability was measured using MTT assay. The cell cycle phase was detected with flow cytometric analysis. Cell cycle-associated proteins were examined using Western blot analysis. MCF-7 breast cancer xenografts were established to monitor tumor growth and cell cycle-associated protein expression. Curcumin inhibited MCF-7 breast cancer cell viability in a concentration-dependent manner (IC(50) value=40 μmol/L). Similarly, MMC inhibited the cell viability with an IC(50) value of 5 μmol/L. Combined treatment of MMC and curcumin showed a synergistic antiproliferative effect. In the presence of curcumin (40 μmol/L), the IC(50) value of MMC was reduced to 5 μmol/L. In MCF-7 xenografts, combined administration of curcumin (100 mg/kg) and MMC (1-2 mg/kg) for 4 weeks produced significantly greater inhibition on tumor growth than either treatment alone. The combined treatment resulted in significantly greater G(1) arrest than MMC or curcumin alone. Moreover, the cell cycle arrest was associated with inhibition of cyclin D1, cyclin E, cyclin A, cyclin-dependent kinase 2 (CDK2) and CDK4, along with the induction of the cell cycle inhibitor p21 and p27 both in MCF-7 cells and in MCF-7 xenografts. These proteins were regulated through p38 MAPK pathway. The results suggest that the combination of MMC and curcumin inhibits MCF-7 cell proliferation and cell cycle progression in vitro and in vivo via the p38 MAPK pathway.

Trabeculectomy with double low dose of mitomycin C – two years of follow-up

PurposeTo evaluate the efficacy and the safety of a surgical technique in which classic trabeculectomy ab externo is performed with a double application of low-dose mitomycin C (MMC) in uncontrolled open-angle glaucoma (OAG) patients.MethodA consecutive series of 43 white patients (43 eyes) with uncontrolled primary OAG underwent trabeculectomy surgery. A double application of MMC (0.1%) was performed: the first under the Tenon’s capsule for 3 minutes, and the second below the scleral flap for 1 or 2 minutes, according to the risk factors. Complete success was defined as intraocular pressure (IOP) <14 mmHg without any additional glaucoma surgery or medication. Qualified success was defined as IOP <14 mmHg with additional needling revision.ResultsMean preoperative IOP was 29.9 mmHg (SD 3.8) for all eyes evaluated. At 1 day postoperative, mean IOP was 6.7 mmHg (SD 1.26). At the end of the first 2 weeks postoperative, mean IOP was 8.6 mmHg (SD 1.7), at 12 months mean IOP was 11.3 mmHg (SD 1.4; P < 0.0001) and at 24 months mean IOP was 11.4 mmHg (SD 1.5; P < 0.0001). At 3 months, two eyes (5.4%) underwent needling of the bleb for cystic blebs formation.ConclusionIn this study we presented the results after 2 years of follow-up of OAG undergoing trabeculectomy with dual administration of MMC (0.1 mg/mL). After 24 months, complete success was achieved in 93% of patients and a qualified success in 100% of patients.

Enhanced antitumor effect of combination intravesical mitomycin C and bacillus Calmette-Guerin therapy in an orthotopic bladder cancer model

Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is currently the most successful adjuvant agent for the treatment and/or prophylaxis of non-muscle-invasive bladder cancer (NMIBC). However, NMIBCs recur in 60-70% of cases and 30% of these recurrent tumors present with a higher grade and more invasive properties. Patients that do not respond to intravesical BCG therapy are considered to be a challenge for urologists. Thus, novel conservative possibilities should be explored. To test the efficacy of a novel therapeutic approach, we examined the antitumor effect of combination therapy by intravesical administration of mitomycin C (MMC) plus BCG, infusing the two drugs simultaneously, in an orthotopic bladder cancer model. Intravesical BCG and MMC administration showed a dose-dependent survival (n=8 per group). The combination of MMC and BCG provided a significant survival advantage compared to the BCG-alone (p=0.035) and MMC-alone groups (p=0.040) (n=8 per group). The group with combined MMC/BCG exhibited a survival period similar to that achieved with an amount eight times higher that of BCG (n=10 per group). Ki-67 labeling index of cancer cells, showing tumor proliferation, was significantly lower in the combined group compared to the BCG-alone (p<0.05), MMC-alone (p<0.01) and control groups (p<0.01). No difference was detected between the combined group and the BCG-alone group with regard to CD3, T-cell infiltration and CD68 macrophage activity. The combined MMC/BCG treatment decreased the tumor appearance rate, improved the survival period and reduced the cellular proliferation rate in tumors compared to the BCG-alone treatment. The results suggest that the combined intravesical MMC/BCG treatment induced an enhanced antitumor effect against bladder tumors. The combined MMC/BCG treatment also showed a survival period similar to that achieved using a dose eight times higher of BCG-alone.

Phase I Clinical Trial and Pharmacokinetics of Intravesical Mitomycin C in Dogs with Localized Transitional Cell Carcinoma of the Urinary Bladder

Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs. The most frequent cause of death is urinary obstruction from the primary tumor. Standard medical therapy for TCC is only partially effective. Intravesical administration of mitomycin C (MMC) in dogs with invasive TCC will result in antitumor activity against the primary tumor and minimal systemic drug absorption. Thirteen privately owned dogs with naturally occurring, histopathologically diagnosed TCC of the urinary bladder. A prospective phase I trial was performed. MMC was given intravesically (600 μg/mL initial concentration) for 1 h/d for 2 consecutive days each month. The MMC concentration was escalated to a maximum of 800 μg/mL in groups of 3 dogs until the maximum tolerated dose (MTD) was determined. Serum assays for MMC were performed to determine the extent of systemic absorption of the MMC. The MTD of MMC based on local toxicoses was 700 μg/mL (1-h dwell time, 2 consecutive days). In addition, 2 dogs had severe myelosuppression and appeared to have systemic absorption of MMC. Five dogs had partial remission, and 7 dogs had stable disease. Intravesical MMC has antitumor activity in dogs with invasive TCC. Further study is needed to determine the cause of the myelosuppression associated with MMC administration, and to develop strategies to minimize this risk.

Increasing Medical Staff Safety by Using a Closed System for Intravesical Instillation of Mitomycin C

Intravesical treatment with mitomycin C (MMC) after trans-urethral resection of bladder tumor is indicated by the guidelines of the European Association of Urology and the American Urology Association. MMC solution is highly irritative to skin and mucous membranes and may be of potential harm to staff handling it. We describe a closed-system device that we have developed for MMC intravesical instillation immediately after transurethral resection of bladder tumor (TURBT) for bladder cancer. A design was developed based on three requirements of a closed system for intravesical instillation of cytotoxic drug: (1) the connection of the system with the MMC administration device (e.g., syringe) must prevent any spillage or spraying of the drug solution. (2) the system should automatically close in the absence of a syringe at the connecting hub.(3) the system should have a draining mode to enable rapid drug and urine drainage into a commercially available urine bag using conventional attachments. In the system developed, MMC syringe is screwed to the connector. The valve is directed to the urinary bladder, and the MMC is injected. At the end of the therapy, the valve is directed to the collecting bag and the MMC and connector are disposed according to the guidelines for hazardous material disposal. To our knowledge, this is the first report of a closed system specifically designed to reduce staff exposure during instillation of MMC. No single case of MMC spill or occupational exposure has been reported since the closed system was introduced.

Reduced Application Time for Prophylactic Mitomycin C in Photorefractive Keratectomy

To determine whether the duration of mitomycin C (MMC) 0.02% application affects visual outcome or the incidence of subepithelial haze in patients undergoing photorefractive keratectomy (PRK) with prophylactic administration of MMC. Retrospective, comparative case series. Two hundred sixty-nine eyes undergoing PRK. This was a retrospective comparative case series that included 269 eyes that underwent PRK with prophylactic MMC application for 120 seconds (group 1, n = 74), 60 seconds (group 2, n = 36), or 12 seconds (group 3, n = 159). The mean preoperative spherical equivalent was -6.49 diopters (D) in group 1, -6.77 D in group 2, and -7.10 D in group 3. Photorefractive keratectomy was performed using a modified nomogram. All eyes received a single intraoperative application of MMC (0.02%) after laser ablation for the above specified durations. Best-corrected visual acuity and corneal haze score. Best-corrected visual acuity was 20/23 in group 1, 20/20 in group 2, and 20/21 in group 3. The mean haze score+/-standard deviation (scale, 0.00-4.00) was 0.11+/-0.31 in group 1, 0.14+/-0.28 in group 2, and 0.07+/-0.20 in group 3 throughout a mean follow-up of 31 months in group 1, 16 months in group 2, and 10 months in group 3. No eyes had a haze score of more than 1.00. There was no statistically significant difference in postoperative best-corrected visual acuity or haze scores among the 3 groups. Administration of prophylactic MMC 0.02% for 12 seconds after PRK seems to be equally efficacious for haze prophylaxis when compared with longer application times of 60 and 120 seconds.

Intra-hepatic Mitomycin C bolus infusion in the treatment of extensive liver metastases of breast cancer

In the treatment of extensive liver metastasis of breast cancer (LMBC), locally administered Mitomycin C (MMC) to the liver might be an effective approach with limited toxicity. We retrospectively reviewed the records of 30 patients with LMBC treated with intra-hepatic MMC at our institution. MMC (12 mg) was administered by transcatheter bolus infusion into the hepatic arteries every 4 weeks. Tumour response according to RECIST criteria, progression free survival (PFS), overall survival (OS) and duration of response (DR) were used to evaluate efficacy. There was a local response in the liver and a global response in respectively 33 and 26%. The median PFS, DR and OS were 3, 4 and 7 months, respectively. There was more benefit in patients without documented metastases outside the liver and without severe liver dysfunction. Thrombocytopenia, leucocytopenia and an allergic reaction were observed after MMC administration in 20 (67%), 12 (40%) and 4 patients (13%), respectively. Intra-hepatic MMC bolus infusion as treatment of extensive LMBC is associated with limited toxicity and has a significant response rate in the liver. Prospective investigations are required to define the place of this modality for treating patients with breast cancer liver metastases.

Effect of Mitomycin C on the Corneal Endothelium When Used for Corneal Subepithelial Haze Prophylaxis Following Photorefractive Keratectomy

To evaluate the potential effect of topical mitomycin C (MMC) on the corneal endothelium of myopic patients undergoing photorefractive keratectomy (PRK). Sixteen eyes with a planned ablation depth >75 microm underwent PRK followed by 0.02% MMC applied for 12 seconds using a methylcellulose sponge. Endothelial specular microscopy was performed with the Keeler-Konan specular photomicroscope in 16 eyes before and at least 1 year after surgery. Mean follow-up was 18 months (range: 12 to 24 months). Mean cell density, coefficient of variation of mean cell area, and percentage of hexagonal cells were measured and calculated using computerized morphometric analysis. Mean endothelial cell densities before and after surgery were 2882 +/- 783 cells/mm2 (range: 1511 to 4022 cells/mm2) and 2867 +/- 588 cells/mm2 (range: 1638 to 3881 cells/mm2), respectively (P > .05). Mean coefficient of variation before and after surgery was 0.30 +/- 0.07 (range: 0.23 to 0.49) and 0.26 +/- 0.04 (range: 0.22 to 0.33), respectively (P=.06). Mean percentage of hexagonal cells before and after surgery was 61% +/- 6.8% (range: 47% to 70%) and 66% +/- 6.7% (range: 54% to 75%), respectively. Administration of MMC for haze prophylaxis following PRK did not have a significant effect on quantitative endothelial cell density or qualitative morphometric parameters in this study.

The hollow fibre model - facilitating anti-cancer pre-clinical pharmacodynamics and improving animal welfare

We describe a modified hollow fibre assay (HFA) for investigating the potential of novel molecules as pharmaceutical agents. In particular the assay provides drug/target interaction data that can facilitate the selection of lead compounds for further evaluation in more sophisticated solid tumour models, whilst successfully implementing the 3Rs - the 'replacement' 'refinement' and 'reduction' of animals. This more ethical and rapid approach to early drug development does not compromise on the validity, sensitivity, predictivity or efficacy of preclinical evaluation. We present novel data using the standard cross-linker mitomycin C (MMC) as a positive control, and two investigational DNA interactive molecules (C1311/ SJG-136). Tumour cells were seeded in fibres and implanted into mice. Following treatment with an intraperitoneal injection, fibres were excised and cells retrieved for pharmacodynamic analysis using the comet assay/fluorescence microscopy. Microscopy results revealed nuclear uptake and localisation within cytoplasmic organelles of HT29 colorectal adenocarcinoma cells following treatment with C1311 (150 mg/kg). Following treatment with SJG-136 (0.3 mg/kg) a 27.3% (p<0.001) DNA cross-linking (s.c.) effect was observed in the HL60 acute promyelocytic leukaemia cell line. DNA cross-linking effects of 55% (i.p) and 50% (s.c.) (p<0.005) were observed in the A549 lung carcinoma cell line following administration of MMC (6 mg/kg). These data are consistent with previous activity defined using solid tumour models, and support the use of the HFA for in vivo pharmacodynamic investigation whilst significantly reducing animal numbers and the influence of tumour growth on the welfare of mice.