Cell Proliferation and DNA Content in Rat Urothelial Lesions after Repeat Intravesical Instillations of Mitomycin C and Bacillus Calmette-Guérin

Abstract

Aim: To study cell proliferation and DNA content in urothelial lesions identified after repeated intravesical instillations of mitomycin C (MMC) and bacillus Calmette-Guérin (BCG) in normal rat urothelium. Material and Methods: A total of 45 rats were divided into nine equal groups: those intravesically instilled with MMC; those receiving BCG intravesically, and a control group intravesically instilled with a physiological solution of sodium chloride (SF). Animals were killed 1, 4 or 8 weeks after the last intravesical instillation. An immunohistochemical streptavidin-biotin-peroxidase technique was performed to investigate Ki-67 expression and the DNA ploidy status was measured using static cytometry. Results: In urothelium exposed to MMC lesions such as simple hyperplasia, dysplasia, carcinoma in situ(CIS), and squamous cell metaplasia were identified. The proliferation index presented values of 11.73, 22.43 and 31.46% in hyperplasias, dysplasias, and CIS, respectively (p < 0.05). The frequency of abnormal DNA content amongst those animals exhibiting simple hyperplasias 25% were aneuploid, in the dysplasia 85.2% were aneuploid (p = 0.041). CIS were all multiploid, and squamous cell metaplasias were all diploid. Animals treated with BCG and SF presented no urothelial lesions and a diploid DNA content. Conclusions: The aneuploid and multiploid DNA content and proliferation index observed in urothelial lesions identified after repeated intravesical instillations of MMC reflect a high degree of genomic instability in such lesions which in itself may lead to rapid regeneration of new phenotypes.

Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study

“…Studies have revealed that histamine is often present in high concentrations in the plasma and tumor tissues of patients with cancer ( 17 , 18 ). In an in vivo study using a melanoma xenograft model ( 19 ) and an in vitro study using mouse spleen cells ( 20 ), histamine was found to promote cancer progression by inducing cell proliferation and activating the regulatory T cells responsible for immune suppression. In contrast, cancer cells frequently upregulate the histamine-synthesizing enzyme l-histidine decarboxylase, leading to increased histamine levels in patients with cancer ( 21 , 22 ).…”

Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study

“…Studies have revealed that histamine is often present in high concentrations in the plasma and tumor tissues of patients with cancer ( 17 , 18 ). In an in vivo study using a melanoma xenograft model ( 19 ) and an in vitro study using mouse spleen cells ( 20 ), histamine was found to promote cancer progression by inducing cell proliferation and activating the regulatory T cells responsible for immune suppression. In contrast, cancer cells frequently upregulate the histamine-synthesizing enzyme l-histidine decarboxylase, leading to increased histamine levels in patients with cancer ( 21 , 22 ).…”

Systematic Review and Cumulative Analysis of the Combination of Mitomycin C plus Bacillus Calmette-Guérin (BCG) for Non–Muscle-Invasive Bladder Cancer

“…So far, several studies 8–13 have investigated the antitumor effect of combined intravesical MMC plus BCG instillation. Lan et al .…”

“…Therefore, advanced adjuvant regimens are necessary to improve the efficacy. Combination of intravesical MMC plus BCG instillation, a novel adjuvant therapy, has been researched in a variety of studies and showed a more enhanced antitumor effect 8, 9 . Detailed combined regimens, drug doses and therapeutic courses varied among these studies, which brought different results 10–13 .…”

Bacillus Calmette-Guérin versus Gemcitabine for Intravesical Therapy in High-Risk Superficial Bladder Cancer: A Randomised Prospective Study

“…To evaluate the possible role of gemcitabine in treating high-risk superficial bladder cancer, it is also important to consider the excellent topical and systemic tolerability of this drug compared to BCG and other drugs that are commonly used for intravesical therapy [22] .…”

Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study

“…Studies have revealed that histamine is often present in high concentrations in the plasma and tumor tissues of patients with cancer ( 17 , 18 ). In an in vivo study using a melanoma xenograft model ( 19 ) and an in vitro study using mouse spleen cells ( 20 ), histamine was found to promote cancer progression by inducing cell proliferation and activating the regulatory T cells responsible for immune suppression. In contrast, cancer cells frequently upregulate the histamine-synthesizing enzyme l-histidine decarboxylase, leading to increased histamine levels in patients with cancer ( 21 , 22 ).…”

Systematic Review and Cumulative Analysis of the Combination of Mitomycin C plus Bacillus Calmette-Guérin (BCG) for Non–Muscle-Invasive Bladder Cancer

“…So far, several studies 8–13 have investigated the antitumor effect of combined intravesical MMC plus BCG instillation. Lan et al .…”

“…Therefore, advanced adjuvant regimens are necessary to improve the efficacy. Combination of intravesical MMC plus BCG instillation, a novel adjuvant therapy, has been researched in a variety of studies and showed a more enhanced antitumor effect 8, 9 . Detailed combined regimens, drug doses and therapeutic courses varied among these studies, which brought different results 10–13 .…”

Bacillus Calmette-Guérin versus Gemcitabine for Intravesical Therapy in High-Risk Superficial Bladder Cancer: A Randomised Prospective Study

“…To evaluate the possible role of gemcitabine in treating high-risk superficial bladder cancer, it is also important to consider the excellent topical and systemic tolerability of this drug compared to BCG and other drugs that are commonly used for intravesical therapy [22] .…”

Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study

“…Studies have revealed that histamine is often present in high concentrations in the plasma and tumor tissues of patients with cancer ( 17 , 18 ). In an in vivo study using a melanoma xenograft model ( 19 ) and an in vitro study using mouse spleen cells ( 20 ), histamine was found to promote cancer progression by inducing cell proliferation and activating the regulatory T cells responsible for immune suppression. In contrast, cancer cells frequently upregulate the histamine-synthesizing enzyme l-histidine decarboxylase, leading to increased histamine levels in patients with cancer ( 21 , 22 ).…”

Systematic Review and Cumulative Analysis of the Combination of Mitomycin C plus Bacillus Calmette-Guérin (BCG) for Non–Muscle-Invasive Bladder Cancer

“…So far, several studies 8–13 have investigated the antitumor effect of combined intravesical MMC plus BCG instillation. Lan et al .…”

“…Therefore, advanced adjuvant regimens are necessary to improve the efficacy. Combination of intravesical MMC plus BCG instillation, a novel adjuvant therapy, has been researched in a variety of studies and showed a more enhanced antitumor effect 8, 9 . Detailed combined regimens, drug doses and therapeutic courses varied among these studies, which brought different results 10–13 .…”

Bacillus Calmette-Guérin versus Gemcitabine for Intravesical Therapy in High-Risk Superficial Bladder Cancer: A Randomised Prospective Study

“…To evaluate the possible role of gemcitabine in treating high-risk superficial bladder cancer, it is also important to consider the excellent topical and systemic tolerability of this drug compared to BCG and other drugs that are commonly used for intravesical therapy [22] .…”