Mycobacterial Cell wall-DNA Complex Research Articles

BCG-refractory vs. BCG-relapsing non–muscle-invasive bladder cancer: A prospective cohort outcomes study

PurposePatients with recurrent or persistent high-grade non–muscle-invasive bladder cancer after bacille Calmette-Guérin (BCG) therapy are termed “BCG failures.” We hypothesize that BCG-refractory patients who fail to respond to BCG have worse outcomes after bladder-sparing treatments compared with BCG-relapsing patients whose tumors recur after at least a 6-month disease-free interval. Materials and methodsWe screened 32 patients who had failed BCG therapy for eligibility in a multicenter investigational trial. BCG-refractory patients received instillations of a mycobacterial cell wall–DNA complex extract. BCG-relapsing patients were treated with additional BCG or other intravesical agents. Both groups of patients were followed prospectively with transurethral biopsy after 6 months, and cystoscopy every 3 to 6 months for more than 2 years. Median follow-up time for all patients was 53 months (range: 24–72mo). ResultsSeventeen patients were classified as BCG refractory and 15 patients defined BCG relapsing. Recurrence-free median survival time was 10 months for BCG-refractory patients receiving mycobacterial cell wall–DNA complex vs. 23 months for BCG-relapsing patients who received another induction course of BCG therapy (P = 0.002). Progression-free survival time was 18 months for BCG-refractory vs. 52 months for BCG-relapsing patients (P = 0.001). Of the 17 BCG-refractory patients, 8 (47%) have died vs. 3 (20%) of the 15 BCG-relapsing patients. ConclusionsBCG-refractory and BCG-relapsing categories differentiate BCG-failed patients into high-and lower-risk prognostic groups that may be useful in guiding treatment strategies.

1783 SAFETY OF INTRAVESICAL MYCOBACTERIAL CELL WALL-DNA COMPLEX GIVEN IMMEDIATELY POSTSURGERY IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER

• IVe bacillus Calmette-Guerin (BCG) is preferred for treatment of NMIBC with elevated risk of progression.1,3 – However, BCG cannot be instilled until at least 2 weeks (Figure 1) after surgery because of risk of serious complications (eg, sepsis).1-3 • Mycobacterial cell wall–DNA complex (MCC), a sterile suspension of cell wall and DNA fragments derived from the nonpathogenic Mycobacterium phlei, has recently been shown to reduce recurrences in patients for whom BCG previously failed.5,6 – MCC exhibits a dual mechanism of action, with immunomodulatory and chemotherapeutic effects (Figure 2).7,8

Mycobacterial cell wall-DNA complex induces apoptosis in cancer cells

Mycobacterial cell wall-DNA complex induces apoptosis in cancer cells

Preventing Bladder Tumor Implantation With Photodynamic Therapy in a Rat Model Mimicking Post-Fluorescence Guided Transurethral Resection

Fluorescence guided transurethral resection has gained acknowledgment from the urological community and it is progressively becoming more applied. It has been shown to decrease the recurrence rate of nonmuscle invasive bladder cancer due to incomplete resection due to lack of visualization. The implantation of viable tumor cells seeded during transurethral resection is another reason for recurrence. We investigated whether applying photodynamic therapy on sensitized tumor cells would decrease the amount of viable intraluminal cells and tumor cell implantation. Two models were designed to mimic the situation after fluorescence guided transurethral resection, including partly or fully de-epithelialized bladders and circulating tumor cells loaded with protoporphyrin IX. Photodynamic therapy was performed. Controls consisted of no drug with no light, light only and drug only. Immediately after photodynamic therapy the intravesical contents were retrieved and clonogenic assays were performed on cells. Bladders were harvested 10 days after cell administration and subjected to pathological analysis. In the photodynamic therapy and control groups tumor volume was proportional to the instilled cell load. Clonogenic assays showed that viable cells were decreased a tenth of the initial administered amount. Tumor implantation decreased to less than a fifth of control values. Photodynamic therapy can effectively decrease the amount of viable tumor cells in the bladder lumen. This results in a significant decrease in tumor implantation. This technique could possibly be used to further decrease the recurrence rate of nonmuscle invasive bladder cancer.

Intravesical Mycobacterial Cell Wall-DNA Complex in the Treatment of Carcinoma In Situ of the Bladder After Standard Intravesical Therapy Has Failed

We assessed the clinical efficacy and safety of mycobacterial cell wall-DNA complex after intravesical administration in patients with carcinoma in situ in whom prior therapy with bacillus Calmette-Guerin failed or in those who were treatment naïve. Patients received 6 weekly instillations of 4 or 8 mg mycobacterial cell wall-DNA complex (formulated as an emulsion) followed by 3 weekly instillations at weeks 12 and 24. Efficacy and safety were evaluated throughout the treatment phase and at months 12 and 18. A total of 55 patients (mean age 74 years, 74.6% male) received 4 mg (25) or 8 mg (30) mycobacterial cell wall-DNA complex emulsion. All patients were previously treated with bacillus Calmette-Guerin except for 8 who were treatment naïve and 2 who received chemotherapy. In the intent to treat population the complete response rate was 27.3% at weeks 12 and 26 in the 4 mg group while 46.4% of patients receiving 8 mg had a complete response at both points. Mycobacterial cell wall-DNA complex was well tolerated by both dose groups. Overall 90% of all adverse events were mild to moderate in severity. Mycobacterial cell wall-DNA complex has shown antineoplastic activity in patients with bladder cancer with less toxicity than that associated with bacillus Calmette-Guerin administration. The tolerance and efficacy of mycobacterial cell wall-DNA complex might hold promise for the treatment of carcinoma in situ of the bladder.

MP-2.07: The Antiproliferative Activity of MCC (Mycobacterial Cell Wall-DNA Complex) is Independent of p53 Mutational Status, p21 Gene Polymorphisms, Aneuploidy of Chromosomes 3, 7 and 17, and Loss of 9p21 Locus in Bladder Cancer Cell Lines

MP-2.07: The Antiproliferative Activity of MCC (Mycobacterial Cell Wall-DNA Complex) is Independent of p53 Mutational Status, p21 Gene Polymorphisms, Aneuploidy of Chromosomes 3, 7 and 17, and Loss of 9p21 Locus in Bladder Cancer Cell Lines

POD-7.12: Impact of Age on the Ability of Mycobacterial Cell Wall-DNA Complex (MCC) to Induce Urinary Biological Response Markers in Patients with Non-muscle Invasive Bladder Cancer

POD-7.12: Impact of Age on the Ability of Mycobacterial Cell Wall-DNA Complex (MCC) to Induce Urinary Biological Response Markers in Patients with Non-muscle Invasive Bladder Cancer

883: The Anticancer Activity of Mycobacterial Cell Wall-DNA Complex (MCC) Against Human Bladder Cancer Cell Lines is Different to BCG

883: The Anticancer Activity of Mycobacterial Cell Wall-DNA Complex (MCC) Against Human Bladder Cancer Cell Lines is Different to BCG

Mycobacterial Cell Wall-DNA Complex (MCC) for the treatment of carcinoma in situ of the bladder: Non-clinical and clinical phase I-II results

4587 Background: We report on MCC preclinical activity and the results from 2 clinical trials in patients with carcinoma in situ of the bladder (CIS). Methods: Immune stimulatory and anti-cancer activities of MCC were determined; toxicology profile following intravesical and intravenous administration was characterized. Clinical efficacy and safety were evaluated in two trials where 128 patients with CIS associated or not with papillary tumors (<T2) received MCC (4 or 8 mg). Patients received 6 weekly intravesical instillations and a maintenance treatment of up to 10 months. Safety was evaluated by adverse events (AEs); complete response (CR) was defined as negative biopsy, cystoscopy and cytology. Results: Apoptosis and inhibition of proliferation were shown in vitro in bladder cancer ATCC cell lines and in human bladder tumour cells in primary culture. Immuno-stimulation was seen in human PBMC. In toxicology studies MCC was non toxic intravenously at a human equivalent dose up to 4.32 mg/kg. In 2 clinical studies MCC was well tolerated by all patients with 20–37% drug related AEs and less than 1% drug-related SAEs. The CR rates were 63%, 49% and 41% at weeks 12, 24 and 60 for the phase I study. For the phase II study, the CR rates at weeks 12, 26, months 12 and 18 in the ITT population were 27%, 27%, 32% and 23% at a dose of 4 mg and 46%, 46%, 64% and 73% at a dose of 8 mg. Increases in urinary cytokines and apoptosis markers were observed in the majority of patients. Conclusions: Pre-clinical and clinical data demonstrated anticancer activity of MCC, clinical efficacy and an excellent safety profile. MCC is different from and has a different mechanism of action than BCG, the standard treatment for CIS. A multicenter phase 3 trial is being set up to confirm the efficacy and safety of MCC at a dose of 8 mg. No significant financial relationships to disclose.

761: Antiproliferative and Pro-Apoptotic Effects of Mycobacterial Cell Wall-DNA Complex on Human Bladder Tumor Cells in Primary Culture

761: Antiproliferative and Pro-Apoptotic Effects of Mycobacterial Cell Wall-DNA Complex on Human Bladder Tumor Cells in Primary Culture

Antitumor Activity of Mycobacterial Cell Wall‐DNA Complex (MCC) Against Canine Urinary Bladder Transitional Cell Carcinoma Cells

Introduction: Mycobacterial cell wall‐DNA complex (MCC) is a bifunctional anticancer agent that induces cancer cell apoptosis and stimulates cytokine synthesis by immune cells. Intravesical MCC is currently being evaluated in humans with high‐grade urinary bladder cancer. Evaluation of MCC in dogs with transitional cell carcinoma (TCC) will allow mechanistic studies in a natural animal model of TCC, and a potentially beneficial therapy for dogs with this cancer. In this study, we have determined the anticancer activity of MCC against canine TCC cells in vitro.Methods: Canine TCC cells (K9TCC cell line) were incubated with MCC (0.05–100 μg/ml, 0.5–72 hours). Cellular proliferation was measured by MTT reduction. Cell cycle was analyzed by flow cytometry with propidium iodide. Apoptosis was identified by flow cytometry using anti‐active‐caspase‐3/PE and anti‐cleaved‐PARP/FITC antibodies. Apoptosis‐inducing activity of 100 μg/ml MCC in combination with piroxicam (0.1–1.0 uM) was evaluated.Results: MCC inhibited K9TCC cell proliferation in a concentration‐dependent manner (maximal activity – 45% at 100 μg/ml MCC) in association with the presence of activated caspase‐3 and cleaved PARP. Inhibition of proliferation and apoptosis‐inducing activities of MCC were independent of cell cycle phase. A thirty‐minute exposure of MCC was sufficient for optimal activity. Piroxicam (0.5 uM) enhanced apoptosis‐inducing activity of MCC.Conclusions: MCC induces apoptosis in K9TCC cells. This activity is potentiated by piroxicam. Following positive results in vitro, in vivo studies have been initiated. One dog, treated to date, has had a minor reduction in tumor volume following the first course of treatment with no treatment‐related toxicity.

Effects of Mycobacterial Cell Wall‐DNA Complex (MCC), Alendronate and Pamidronate on Canine Osteosarcoma Cell Lines

Introduction: MCC, a cell wall composition prepared from Mycobacterium phlei., inhibits the proliferation and induces apoptosis in a wide range of tumor cells. Bisphosphonates have been reported to inhibit the proliferation of canine osteosarcoma cell lines. In this study, we have determined the activity of MCC alone and in combination with the bisphosphonates alendronate and pamidronate on canine osteosarcoma cell lines.Methods: Canine osteosarcoma cell lines D17 and D22 were incubated with different concentrations of MCC (0.01–100 μg/ml) and suboptimal concentrations of alendronate and pamidronate for 72 hours. Cellular proliferation was measured by MTT reduction. Nuclear DNA condensation was determined using with Hoescht 33258 staining, and apoptosis by flow cytometry using active‐caspase‐3/PE and anti‐cleaved‐PARP/FITC antibodies.Results: MCC inhibited the proliferation of both canine osteosarcoma D17 and D22 cell lines in a concentration‐dependent manner. The IC50 for D17 cells was 3.9 μg/ml and for D22 cells 44.4 μg/ml. Cells incubated with 100 μg/ml MCC were positive for Hoescht staining, active caspase‐3 and cleaved PARP, indicative of cell death by apoptosis. The addition of alendronate or pamidronate was found to potentiate the apoptosis‐inducing activity of MCC. Maximal activity was observed when 5 μM alendronante or 10 μM pamidronate were used in combination with 100 μg/ml MCC.Conclusion: MCC inhibits the proliferation and induces apoptosis in canine osteosarcoma cell lines in vitro. This anticancer activity can be potentiated by the use of alendronate and pamidronate. These data support the development of MCC as a therapeutic agent for the treatment of canine osteosarcoma.

327Intravesical treatment with mycobacterial cell wall DNA complex (MCC) induces a cytokine profile distinct from BCG

327Intravesical treatment with mycobacterial cell wall DNA complex (MCC) induces a cytokine profile distinct from BCG

71 Mycobacterial cell wall-DNA complex (MCC) interacts rapidly with bladder cancer cells and demonstrates synergy with gemcitabine

71 Mycobacterial cell wall-DNA complex (MCC) interacts rapidly with bladder cancer cells and demonstrates synergy with gemcitabine

468The direct anticancer activity of mycobacterial cell wall-DNA complex (MCC) is not inhibited by anti-MCC antibodies

468The direct anticancer activity of mycobacterial cell wall-DNA complex (MCC) is not inhibited by anti-MCC antibodies

714: Inhibition of Bladder Cancer Cell Proliferation by Mycobacterial Cell Wall-DNA Complex (MCC) in Combination with Chemotherapeutic Agents

You have accessJournal of UrologyDiscussed Poster, Monday, May 10, 2004, 8:00 am - 12:00 pm1 Apr 2004714: Inhibition of Bladder Cancer Cell Proliferation by Mycobacterial Cell Wall-DNA Complex (MCC) in Combination with Chemotherapeutic Agents Myriam Labelle, Mario C. Filion, and Nigel C. Phillips Myriam LabelleMyriam Labelle More articles by this author , Mario C. FilionMario C. Filion More articles by this author , and Nigel C. PhillipsNigel C. Phillips More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)37963-1AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "714: Inhibition of Bladder Cancer Cell Proliferation by Mycobacterial Cell Wall-DNA Complex (MCC) in Combination with Chemotherapeutic Agents." The Journal of Urology, 171(4S), p. 190 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 171Issue 4SApril 2004Page: 190 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Myriam Labelle More articles by this author Mario C. Filion More articles by this author Nigel C. Phillips More articles by this author Expand All Advertisement PDF downloadLoading ...

717: Mycobacterial Cell Wall-DNA Complex (MCC) Induces IgG Antibody Responses Against MCC and BCG in Patients with CIS of the Bladder

717: Mycobacterial Cell Wall-DNA Complex (MCC) Induces IgG Antibody Responses Against MCC and BCG in Patients with CIS of the Bladder

Cell cycle arrest and apoptosis induction in bladder cancer cells by mycobacterial cell wall-DNA complex (MCC) is associated with changes in intracellular signaling

Cell cycle arrest and apoptosis induction in bladder cancer cells by mycobacterial cell wall-DNA complex (MCC) is associated with changes in intracellular signaling

Prolonged treatment of bladder cancer cell lines with mycobacterial cell wall-DNA complex (MCC) does not select a resistant phenotype

Prolonged treatment of bladder cancer cell lines with mycobacterial cell wall-DNA complex (MCC) does not select a resistant phenotype

Cell cycle arresting and apoptosis-inducing activity of mycobacterial cell wall-DNA complex (MCC) towards human bladder cancer cells

Cell cycle arresting and apoptosis-inducing activity of mycobacterial cell wall-DNA complex (MCC) towards human bladder cancer cells