Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study

Donin, Nicholas M.; Duarte, Sandra; Lenis, Andrew T.; Caliliw, Randy; Jr., C.M. Torres; Smithson, Anthony; Strauss-Ayali, Dalit; Agmon-Gerstein, Yael; Malchi, Nadav; Said, Jonathan; Raman, Steven S.; Holden, Stuart; Pantuck, Allan J.; Belldegrun, Arie S.; Chamie, Karim

doi:10.1016/j.urology.2016.09.039

Cited by 36 publications

(37 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prolonged exposure of the tumor to MMC might be more effective and previous studies have shown that increased dwell time of MMC can significantly increase MMC efficacy in vitro and in vivo. 4,5 In a limited number of preclinical studies with hydrogels, all with different physical characteristics, [6][7][8][9][10][11][12] materials were combined with nanoparticles, 6,12 epirubicin, 7 doxorubicin 10 and bacillus Calmette-Guérin (BCG). 11 These studies suggested prolonged exposure or enhanced drug penetration.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the efficacy of repeated instillations of mitomycin C mixed with a thermosensitive hydrogel in an orthotopic rat bladder cancer model

Valenberg

Strauss-Ayali

Agmon-Gerstein

et al. 2018

Therapeutic Advances in Urology

Self Cite

View full text Add to dashboard Cite

Background:We investigated a thermoreversible hydrogel that is highly viscous at body temperature, while fluid-like at a low temperature, thus aiming for a slow and prolonged intravesical drug release. Our study purposed to assess antitumor efficacy of mitomycin C (MMC) mixed with hydrogel in an orthotopic rat bladder cancer model.Methods:Bladders of female Fischer F344 rats were grafted with 1.5 × 106 AY-27 urothelial carcinoma cells. On day 5, tumor presence was assessed by cystoscopy and rats were divided into six groups (five treatment, one control, n = 10/group). Intravesical treatments (0.5 mg or 1 mg MMC-H2O or MMC-hydrogel, or 2 mg MMC-hydrogel) were administered on days 5, 8 and 11. Rats were sacrificed at day 14 and bladders were evaluated.Results:Rats with tumor at cystoscopy (47/60) were evaluated for efficacy. At necropsy, all control animals (8/8) had tumors. No microscopic tumors were present in the 0.5 mg and 1 mg MMC-hydrogel groups compared with 2/8 and 1/8 rats in the 0.5 mg and 1 mg MMC-H2O groups (p = 0.47 and p = 1.00, respectively).Greater toxicity was seen in animals treated with MMC-hydrogel compared with MMC-H2O, as demonstrated by lower body weights at necropsy (p = 0.000) and a tendency for more severe clinical signs in the 1 and 2 mg MMC-hydrogel groups. Rats that died prematurely received 1 mg (4/10) or 2 mg (9/10) of MMC-hydrogel.Conclusions:Under the current model conditions it is unclear whether instillation of MMC-hydrogel is more effective than MMC-H2O. Nonetheless, the observed difference in toxicity, acting as a surrogate marker for systemic MMC exposure in the MMC-hydrogel-treated rats, supports the prolonged drug release mechanism of the hydrogel.

show abstract

Section: Introductionmentioning

confidence: 99%

Assessment of the efficacy of repeated instillations of mitomycin C mixed with a thermosensitive hydrogel in an orthotopic rat bladder cancer model

Valenberg

Strauss-Ayali

Agmon-Gerstein

et al. 2018

Therapeutic Advances in Urology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Most recently, much attention has been gained with the potential applicability of MMC using a thermosensitive polymer to increase the dwell time; however, no clinical data have been released. 27 We postulated that by utilizing a chemotherapeutic agent that does not rely on prolonged dwell times to incite an immunologic and cytokine response in a maintenance regimen, results could be improved. Our study shows a noticeable difference in recurrence, progression, and nephroureterectomy rates for patients depending on whether they were treated through NT or ureteral catheter.…”

Section: Discussionmentioning

confidence: 99%

Induction and Maintenance Adjuvant Mitomycin C Topical Therapy for Upper Tract Urothelial Carcinoma: Tolerability and Intermediate Term Outcomes

Metcalfe

Wagenheim

Xiao

et al. 2017

Journal of Endourology

View full text Add to dashboard Cite

show abstract

“…11 The safety and feasibility of this formulation was tested in a preclinical setting using a Yorkshire swine model. 11 In an eloquent three-phase study design, the authors instilled UGN-101 into swine via percutaneous nephrostomy tubes in various settings, including single administration, incrementally increasing doses, and an alternate administration schedule of six twice-weekly instillations. Pharmacokinetic and imaging data was obtained from all animals, and nephrectomy specimens were used for histologic analysis.…”

Section: Development Safety and Feasibility Of Ugn-101: Preclinical mentioning

confidence: 99%

UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma

Kokorovic

Matin

2020

Ther Adv Med Oncol

View full text Add to dashboard Cite

Upper tract urothelial carcinoma (UTUC) is a rare malignancy. The standard treatment for localized high-risk disease is radical nephroureterectomy, which confers significant morbidity and is not appropriate for all patients. Patients harboring low-risk, non-invasive disease may be candidates for organ-sparing treatment, which includes endoscopic resection with or without intracavitary drug therapy. Successful administration of intracavitary chemotherapy to the upper tracts is impeded by rapid washout of the agent and short dwell times. This has limited the clinical utility of mitomycin C for treatment of upper tract tumors, despite the successful outcomes observed in low-grade urothelial carcinoma of the bladder. Currently, there is an unmet need for development of a technically feasible and oncologically sound intracavitary therapy for management of low-grade UTUC. UGN-101 (Jelmyto™) is a novel formulation of mitomycin C that uses a unique hydrogel designed to increase urinary dwell time, and thereby efficacy of treatment. Preclinical data demonstrated promising results regarding the safety and feasibility of this agent. Preliminary results of a phase III trial (OLYMPUS study) [ClinicalTrials.gov identifier: NCT02793128] demonstrated the efficacy of UGN-101 as a successful chemo-ablative agent for low-grade upper tract tumors. UGN-101 may represent a pivotal paradigm shift in the treatment of low-grade UTUC. Indeed, the drug has recently been granted approval by the US Food and Drug Administration as the first treatment for low-grade UTUC, which may lead to significant improvements in patient care and a long-awaited decrease in the burden of disease.

show abstract

Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study

Cited by 36 publications

References 16 publications

Assessment of the efficacy of repeated instillations of mitomycin C mixed with a thermosensitive hydrogel in an orthotopic rat bladder cancer model

Assessment of the efficacy of repeated instillations of mitomycin C mixed with a thermosensitive hydrogel in an orthotopic rat bladder cancer model

Induction and Maintenance Adjuvant Mitomycin C Topical Therapy for Upper Tract Urothelial Carcinoma: Tolerability and Intermediate Term Outcomes

UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma

Contact Info

Product

Resources

About