Effect Of Intravesical Chemotherapy Research Articles

Thiolated Mesoporous Silica Nanoparticles as an Immunoadjuvant to Enhance Efficacy of Intravesical Chemotherapy for Bladder Cancer.

The characteristics of global prevalence and high recurrence of bladder cancer has led numerous efforts to develop new treatments. The spontaneous voiding and degradation of the chemodrug hamper the efficacy and effectiveness of intravesical chemotherapy following tumor resection. Herein, the externally thiolated hollow mesoporous silica nanoparticles (MSN-SH(E)) is fabricated to serve as a platform for improved bladder intravesical therapy. Enhanced mucoadhesive effect of the thiolated nanovector is confirmed with porcine bladder. The permeation-enhancing effect is also verified, and a fragmented distribution pattern of a tight junction protein, claudin-4, indicates the opening of tight junction. Moreover, MSN-SH(E)-associated reprogramming of M2 macrophages to M1-like phenotype is observedin vitro. The antitumor activity of the mitomycin C (MMC)-loaded nanovector (MMC@MSN-SH(E)) is more effective than that of MMC alone in bothin vitroandin vivo.In addition, IHC staining is used to analyze IFN-γ, TGF-β1, and TNF-α. These observations substantiated the significance of MMC@MSN-SH(E) in promoting anticancer activity, holding the great potential for being used in intravesical therapy for non-muscle invasive bladder cancer (NMIBC) due to its mucoadhesivity, enhanced permeation, immunomodulation, and prolonged and very efficient drug exposure.

Effect of Intravesical Chemotherapy on the Survival of Patients with Non-Muscle-Invasive Bladder Cancer Undergoing Transurethral Resection: A Retrospective Cohort Study Among Older Adults

Background: The average age of diagnosis for bladder cancer is 73 and about 75 percent of all bladder cancers are non-muscle invasive at initial diagnosis. It is recommended that non-muscle invasive bladder cancers (NMIBC) should be treated with transurethral resection of the bladder tumor (TURBT) followed by chemotherapy. However, there is no large-scale study from real-world databases to show the effectiveness of chemotherapy on the survival of older adults with NMIBC that have undergone TURBT. This study aimed to investigate the effects of chemotherapy on survival among older NMIBC patients with TURBT. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015), we performed analyses of cancer-specific mortality and overall mortality comparing chemotherapy versus no chemotherapy after TURBT. Coarsened exact matching was performed to balance the baseline patient characteristics. Cox proportional hazards and Kaplan-Meir analyses were used to evaluate survival outcomes. Results: A total of 3,222 matched patients with 1,611 in each arm (chemotherapy and no chemotherapy) were included in our study. After adjusting for covariates, multivariable Cox regression analyses show chemotherapy was associated with lower cancer-specific mortality (HR 0.63; 95% CI 0.42-0.94; p value 0.024). However, chemotherapy did not have any effect on overall mortality (HR 0.84; 95% CI 0.65-1.07; p value 0.159). The Kaplan-Meier curves show the protective effects of chemotherapy on cancer specific survival (p=0.032), but not on overall survival (p=0.34). Conclusion: Chemotherapy improved cancer specific survival among older patients with non-muscle invasive bladder cancer undergoing TURBT surgery, but it had no effect on overall survival. There is a need for more granular level real-world data on chemotherapy regimens and dosage to effectively investigate the effects of chemotherapy on the survival of older patients with NMIBC that have undergone TURBT.

Preclinical evaluation of a hypotonic docetaxel nanosuspension formulation for intravesical treatment of non-muscle-invasive bladder cancer.

Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure. We compare the bladder residence time and efficacy in an immune-competent rat model of NMIBC to the clinical comparator, solubilized docetaxel (generic Taxotere) diluted for intravesical administration. We found that only the intravesical docetaxel nanosuspension significantly decreased cell proliferation compared to untreated tumor tissues. The results presented here suggest that the combination of nanoparticle-based chemotherapy and a hypotonic vehicle can provide more efficacious local drug delivery to bladder tissue for improved treatment of refractory NMIBC.

Observation of intravesical chemotherapy effect in papillary urothelial neoplasm of low malignant potential urinary bladder after transurethral resection

Objective To observe the effect of intravesical chemotherapy in papillary urothelial neoplasm of low malignant potential (PUNLMP) urinary bladder after transurethral resection of bladder tumor (TUR-Bt). Methods 44 cases of PUNLMP confirmed by pathological examination from Jan 2004 to Dec 2013 were retrospectively analyzed. Clinical manifestation: 24 asymptomatic, 19 gross hematuria and 1 abdominal discomfort. All cases were treated by TUR-Bt and immediately administered by intravesical instillation of 40 mg HCPT once, then 32 cases (A group) underwent additional intravesical instillation of HCPT once, and 12 cases (B group) underwent instillation qw for 8 times. Results PUNLMP cases accouted for 2.28 % (44/1 926) of bladder neoplasms admitted during the same period. There were 32 males and 12 females. 39 patients had multiple tumors, and 5 had single. All of cases were followed up with the medial follow-up time of 82 months (16-136 months), only one case in B group recurred after 14 months, and postoperatively without pathological progression. The difference of recurrence rates between two groups had no statistical significance (P= 0.273). Conclusions PUNLMP has low incidence rate and is more common among middle-aging males. Doctors should consider PUNLMP when patients with bladder neoplasm are asymptomatically detected. Immediate instillation combined with additional one postoperatively could reduce the recurrence rate of PUNLMP obviously with satisfying prognosis. However, maintenance instillation does not enhance effect. Key words: Bladder neoplasms; Chemotherapy, cancer, regional perfusion; Recurrence

Abstract 1341: Rapid decrease of ATP followed by necrosis-like cell death in bladder cancer cells after exposure to high-dose chemotherapeutics used in intravesical therapy

Abstract Objectives) Non-muscle invasive bladder cancer is often treated by intravesical chemotherapy following transurethral resection. Mechanism of the effect of intravesical chemotherapy remains elusive. In this experiment, we studied cell death mechanism induced by high-dose chemotherapeutics using a novel culture method for primary cancer cells. Materials and methods) We have developed a new culture method which enables preparation and culture of primary cancer cells as multicellular spheroids which are termed cancer tissue-originated spheroids (CTOSs) (Okuyama 2013 J Urol). First we generated a bladder cancer patient-derived xenograft. We prepared CTOS from the xenograft, and exposed to high-dose (1mg/ml) or low-dose (0.01mg/ml) of epirubicin (e-ADM) or mitomycin C (MMC) for 2 hours. We investigated absorption of chemotherapeutics into CTOSs and assessed the mode of cell death. Next, we prepared CTOSs directly from surgical specimens of bladder cancer and tested the individual responses after exposure to high-dose e-ADM and MMC. Results) At high dose, e-ADM was promptly and homogenously delivered into cancer cells in the CTOSs. High-dose e-ADM and MMC decreased ATP levels in CTOSs within an hour accompanied with mitochondrial swelling and reduction of mitochondrial membrane potential, while plasma membrane integrity was mainteined. Some of the molecules in mitochondrial apoptotic pathway were subsequently activated, while at later time point the cells lost integrity of cell membrane without DNA laddering. In contrast, CTOSs exposed to low-dose of e-ADM or MMC exhibited typical DNA laddering. Intriguingly, the decrease of ATP levels by e-ADM and MMC was varied among CTOSs derived from 20 surgical specimens. Conclusions) High-dose chemotherapeutics used in intravesical therapy may induce necrosis-like cell death, different from typical apoptosis caused by chemotherapeutics at the dose of systemic chemotherapy. Each bladder cancer may have a different response to high-dose chemotherapeutics used in intravesical therapy, indicating necessity of chemosensitivity test aiming for personalized medicine. Citation Format: Takahiro Yoshida, Hiroaki Okuyama, Masashi Nakayama, Kazuo Nishimura, Norio Nonomura, Masahiro Inoue. Rapid decrease of ATP followed by necrosis-like cell death in bladder cancer cells after exposure to high-dose chemotherapeutics used in intravesical therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1341. doi:10.1158/1538-7445.AM2014-1341

243 Glycan modification of podoplanin enhances growth factor production through stabilization of platelet aggregation in bladder cancer cell

INTRODUCTION AND OBJECTIVES: Non-muscle invasive bladder cancer is often treated by intravesical chemotherapy following transurethral resection. Mechanism of the effect of intravesical chemotherapy has yet to be elucidated. In this study, we investigated cell death mechanism induced by high-dose chemotherapeutics using a newly-developed culture method for primary cancer cells. METHODS: We have developed a novel culture method which enables preparation and culture of primary cancer cells as multicellular spheroids which are termed cancer tissue-originated spheroids (CTOSs) (Okuyama 2013 J Urol). First we generated a bladder cancer patient-derived xenograft. We prepared CTOSs from the xenograft, and exposed to high-dose (1mg/ml) of epirubicin (e-ADM) or mitomycin C (MMC) for 2 hours, or low-dose (0.01mg/ml) of those chemotherapeutics. We investigated absorption of chemotherapeutics into CTOSs and assessed the mode of cell death. Next, we prepared CTOSs directly from surgical specimens of bladder cancer and tested the individual responses after exposure to high-dose e-ADM and MMC. RESULTS: At high dose, e-ADM was promptly and homogenously delivered into cancer cells in the CTOSs. High-dose e-ADM and MMC decreased ATP levels in CTOSs within an hour accompanied with mitochondrial swelling and reduction of mitochondrial membrane potential, while plasma membrane integrity was maintained. Some of the molecules in mitochondrial apoptotic pathway were subsequently activated, while at later time point the cells lost integrity of cell membrane without DNA laddering. In contrast, CTOSs exposed to low-dose of eADM or MMC exhibited typical DNA laddering. Intriguingly, the decrease of ATP levels was varied among CTOSs derived from 20 surgical specimens. CONCLUSIONS: High-dose chemotherapeutics used in intravesical therapy may induce necrosis-like cell death, different from typical apoptosis caused by chemotherapeutics at the dose of systemic chemotherapy. Each bladder cancer may have a different response to high-dose chemotherapeutics used in intravesical therapy, indicating necessity of chemosensitivity test aiming for personalized medicine.

MP21-07 HIGH-DOSE CHEMOTHERAPEUTICS USED IN INTRAVESICAL THERAPY INDUCE MITOCHONDRIAL DYSFUNCTION FOLLOWED BY NECROSIS-LIKE CELL DEATH IN BLADDER CANCER CELLS

INTRODUCTION AND OBJECTIVES: Non-muscle invasive bladder cancer is often treated by intravesical chemotherapy following transurethral resection. Mechanism of the effect of intravesical chemotherapy has yet to be elucidated. In this study, we investigated cell death mechanism induced by high-dose chemotherapeutics using a newly-developed culture method for primary cancer cells. METHODS: We have developed a novel culture method which enables preparation and culture of primary cancer cells as multicellular spheroids which are termed cancer tissue-originated spheroids (CTOSs) (Okuyama 2013 J Urol). First we generated a bladder cancer patient-derived xenograft. We prepared CTOSs from the xenograft, and exposed to high-dose (1mg/ml) of epirubicin (e-ADM) or mitomycin C (MMC) for 2 hours, or low-dose (0.01mg/ml) of those chemotherapeutics. We investigated absorption of chemotherapeutics into CTOSs and assessed the mode of cell death. Next, we prepared CTOSs directly from surgical specimens of bladder cancer and tested the individual responses after exposure to high-dose e-ADM and MMC. RESULTS: At high dose, e-ADM was promptly and homogenously delivered into cancer cells in the CTOSs. High-dose e-ADM and MMC decreased ATP levels in CTOSs within an hour accompanied with mitochondrial swelling and reduction of mitochondrial membrane potential, while plasma membrane integrity was maintained. Some of the molecules in mitochondrial apoptotic pathway were subsequently activated, while at later time point the cells lost integrity of cell membrane without DNA laddering. In contrast, CTOSs exposed to low-dose of eADM or MMC exhibited typical DNA laddering. Intriguingly, the decrease of ATP levels was varied among CTOSs derived from 20 surgical specimens. CONCLUSIONS: High-dose chemotherapeutics used in intravesical therapy may induce necrosis-like cell death, different from typical apoptosis caused by chemotherapeutics at the dose of systemic chemotherapy. Each bladder cancer may have a different response to high-dose chemotherapeutics used in intravesical therapy, indicating necessity of chemosensitivity test aiming for personalized medicine.

Role of P-Glycoprotein in Chemoresistant Superficial Bladder Tumours

The drug resistance at cellular level is mediated by P-glycoprotein (P-G), which is variably expressed in bladder tumours. The effect of intravesical chemotherapy on P-G status was studied in chemoresistant and recurrent superficial tumours which progressed to metastasis or needed further treatment. Archival histological materials of 14 patients who received intravesical epirubicin for recurrent superficial transitional cell carcinoma of the bladder were studied for the presence of P-G using monoclonal antibody JSB-1. Four patients showed complete absence of P-G following chemotherapy although only 2 patients were recurrence-free. In 4 patients with extravesical metastasis, there was no evidence of increased P-G expression. The P-glycoprotein expression is not related to histological grading or clinical progression of bladder tumours.

Intravesical chemotherapy.

A total of 85 cases treated by intravesical administration of adriamycin (ADM) at Okayama University and other cooperating institutions were examined. Instillation of 50 mg adriamycin dissolved in 30 ml physiological saline was performed in two courses of 3 consecutive days, with a 4-day interval between the courses. The response rate was 70.6%. Following instillation therapy transurethral resection (TUR) was carried out in 69 cases (80%), segmental cystectomy in 7, and total cystectomy in 3. The follow-up period averaged 42 months, during which the recurrence rate was 57%; recurrence occurred within 18 months in 80% of these cases. Since the recurrence per patient-month x 100 was 3.348, the precise effect of intravesical chemotherapy in the prevention of recurrence was unclear. There were 9 cases of advanced disease (11% of the total, 18% of cases with recurrence). One patient with CIS (flat invasive tumor) seemingly achieved CR, but died 43 months after treatment due to metastatic disease. While this method is not always indicated in cases of CIS (flat invasive tumor), in cases in which it is indicated a drug causing only limited stimulation of the bladder mucosa should be used and long-term follow-up is essential.

Intravesical chemotherapy. Studies on the relationship between pH and cytotoxicity.

The influence of pH on the antitumor activity of drugs used for intravesical chemotherapy was studied. A human continuous cell line derived from a transitional cell carcinoma of the bladder was exposed to 6 drugs (Adriamycin [doxorubicin], cisplatin, epirubicin, epodyl, mitomycin C, and thiotepa) for 1 hour at 11 pH values ranging from 5.2 to 9.7, and cytotoxicity was measured by inhibition of colony formation. pH had a marked influence on drug activity: cisplatin, mitomycin C, and thiotepa were most cytotoxic in acid media, Adriamycin, and epirubicin in alkaline media, while epodyl was the only drug whose cytotoxicity was unaffected by pH. In addition to these in vitro studies, comparisons were made of the pH of urine samples obtained from patients immediately before and at the completion of intravesical chemotherapy. Changes in pH up to a maximum of +/- 1.6 units were observed, although in most cases, values were similar before and after therapy. All the drugs used were acidic in solution, with the exception of thiotepa. It is concluded that by adjusting solvent and urine pH to the optimum value for each drug, the effectiveness of intravesical chemotherapy might be enhanced.