Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin

ABSTRACT The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy.

Concurrent Down-Regulation of PTEN and NKX3.1 Expression in Iranian Patients with Prostate Cancer

ABSTRACT NKX3.1 and PTEN genes are involved in the development and progression of prostate cancer (PCa). Here, in line with other studies that correlated the expression of these two genes, we aimed at evaluating the expression pattern of these genes in clinical PCa samples. Collectively, 81 tissue samples including 45 human PCa and 36 benign prostatic hyperplasia (BPH) specimens were included in the study. The tissue samples were subjected to RNA extraction and subsequently to cDNA synthesis according to the kit manufacturer's protocol. Quantitative Real-Time PCR assay was performed for each sample in triplicate reactions. REST and SPSS software were used to statistically analyze PTEN and NKX3.1 gene expression data. Expression level of both NKX3.1 and PTEN genes was down-regulated in PCa samples compared to BPH samples. The relative expression ratio of PTEN and NKX3.1 was decreased to 0.155 and 0.003, respectively (P=0.000). The results of Chi-Square analysis revealed a significant correlation between the expression of these genes in both BPH and cancer groups (P=0.004 and 0.001, respectively). According to previous studies and our data, we concluded that the association between the down-regulation of PTEN and NKX3.1 genes contributed to the prostate tumorigenesis. This might highlight the interaction between the proteins encoded by these genes. Furthermore, this finding might be exploited for the development of innovative diagnostic and therapeutic approaches in PCa.

Immunohistochemical phospho tensin tumor suppressor gene staining patterns in endometrial hyperplasias: A 2-year study.

Background: Endometrial carcinoma is a common neoplasm associated with the female genital tract with considerable morbidity.Eendometrial hyperplasias have been widely regarded as precursor lesions. It is of importance to the pathologist to identify the subset of hyperplasias or the associated factor which could be a possible forerunner of malignancy. Phospho tensin gene (PTEN) has gained importance as one of the factors responsible. Aim: To determine the variability in PTEN expression patterns in different types of endometrial hyperplasias. Settings and Design: The study was undertaken on samples received at the Department of Pathology from 2005 to 2007. Materials and Methods: One hundred samples with 76 showing hyperplasias of different types formed the core "study group" with simple hyperplasia without atypia predominating. The rest belonged to the control groups. PTEN intensity and percentage positivity, variability in patterns of glandular and stromal expression, the number and type of PTEN null glands in different types of hyperplasia were evaluated. Statistical analyses used were Fisher's exact test based on Monte Carlo test and chi-square test. Results: Complex hyperplasia was associated with a reduction in number of strongly PTEN positive glands, with an increase in null glands, seen in clusters. Co-existing atypia was associated with the weakest staining and in fewer glands. Conclusions: PTEN expression in endometrial hyperplasias can be used as an early warning of heightened cancer risk and a potential target for preventive treatment. However, extensive research is needed along this line to conclusively establish its effectiveness.

Detection of PTEN immunoreactivity in endometrial hyperplasia and adenocarcinoma.

OBJECTIVE: To investigate PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression in endometrial hyperplasia and adenocarcinoma as analyzed by immunohistochemistry. MATERIAL AND METHOD: PTEN protein expression was evaluated by immunohistrochemical study of 70 paraffin-embedded curettage endometrial tissue samples (10 normal endometrium, 55 endometrial hyperplasia, and 15 endometrial adenocarcinomas) selected from surgical pathology files of the Division of Gynecologic Pathology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, from 2001 to 2004. Intensity of epithelial staining of PTEN immunoreactivity in different histologic types was determined. RESULTS: Absence of PTEN protein expression was detected in 60% of endometrial carcinoma, 60% of atypical endometrial hyperplasia, and 24% of typical endometrial hyperplasia. In endometrial hyperplasia without atypia group, the majority of cases revealed moderate to strong PTEN expression, with 70% in simple hyperplasia and 47% in complex hyperplasia. There is a significant statistical difference of PTEN immunoreactivity among proliferative endometrium, endometrial hyperplasia and endometrial carcinoma group (p = 0.004). CONCLUSION: Complete loss of PTEN protein expression was most commonly found in endometrial carcinoma and hyperplasia with cytologic atypia.