Telomerase activity associated with progression of cervical lesions in a group of Colombian patients / Associação da atividade da telomerase com a progressão de lesões cervicais em um grupo de pacientes da Colômbia

Abstract PURPOSE To analyze the relation between the cytological findings and telomerase activity (TA). METHODS Cervical samples were evaluated and classified according to the Bethesda System. Telomerase activity was measured total product generated values (TPG) using the TRAP assay (telomeric repeat amplification protocol); data were analyzed statistically using the χ2 test, with the level of significance set at p<0.05. RESULTS The study was conducted on 102 patients. Of these, 3.9% showed normal cytological findings, 8.8% showed cervicitis; 2% showed Atypical Squamous Cells of Undetermined Significance (ASCUS); 67.6% showed Low Grade Squamous Intraepithelial Lesion (LSIL); 11.8% showed High Grade Squamous Intraepithelial Lesion (H-SIL) and 5.9% showed Squamous Carcinoma. Among telomerase-positive samples, the TPG values were cervicitis<normal<ASCUS<L-SIL<H-SIL<Carcinoma. CONCLUSION Results show increased telomerase activity with increasing severity of lesion, supporting the association between TA and type of lesion.

Resumo OBJETIVO Analisar a relação entre os achados citológicos e atividade da telomerase (AT). MÉTODOS Amostras cervicais foram avaliadas e classificadas pelo sistema Bethesda. A AT foi medida como valores de produto total gerado (PTG), utilizando o protocolo de amplificação repetida da telomerase (TRAP); os dados foram analisados estatisticamente usando o teste do χ2, com nível de significância de p<0,05. RESULTADOS Cento e dois pacientes foram analisados: 3,9% com achados citológicos normais, 8,8% com cervicite, 2% com células escamosas atípicas de significado indeterminado (ASCUS), 67,6% com lesão escamosa intraepitelial baixo grau (LEI-BG), 11,8 % com lesão intraepitelial escamosa alto grau (LEI-AG) e 5,9% com carcinoma escamoso. Valores PTG para amostras positivas AT foram: cervicite<normal<ASCUS<LEI-BG<LEI-AG<Carcinoma. CONCLUSÃO Os resultados mostram um aumento na AT com o aumento da lesão, sustentando a associação entre a AT e o tipo de lesão.

The Effect of Cyclooxygenase-2 Expression on Tumor Volume Response in Patients Treated with Radiotherapy for Uterine Cervical Cancer

We investigated the correlation between Cyclooxygenase-2 (COX-2) expression and the tumor response in patients with cervical cancer that were treated with curative radiotherapy (RT). Fifty-seven patients with squamous cell carcinoma were treated with concurrent radiochemotherapy (CRCT, n=29) or RT alone (n=28). The response of each patient was evaluated by three serial Magnetic Resonance Imaging examinations: before the start of RT, at four weeks after the start of RT (mid-RT) and at four weeks after the completion of RT (post-RT). Forty-three patients had positive COX-2 expression. The COX-2 negative patients achieved a higher rate of complete response (CR) at mid-RT than did the COX-2 positive patients (28.6% vs. 7.0%, P=0.054), but not at post-RT (64.3% vs. 69.8%). The initial tumor volume was a significant predictor of CR at mid-RT (P=0.003) and post-RT (P=0.004). The multivariate analysis showed that the initial tumor volume (at mid-RT and post-RT) and CRCT (at post-RT) were significant predictors of CR; however, the COX-2 expression was not. In conclusion, the COX-2 expression status has no significant correlation with the tumor response. Further studies on the changes in COX-2 expression levels during RT may be helpful for determination of its role in the tumor response to treatment and patient prognosis.

The expression of cyclooxygenase-2 in cervical cancers and Hela cells was regulated by estrogen/progestogen / 华中科技大学学报（医学）（英德文版）

To investigate the relationship between the expression of cyclooxygenase-2 (COX-2) and menstrual cycle, the regulatory effects of 17-beta-estradiol (E(2)) and medroxyprogesterone acetate (MPA) on the expression of COX-2 in cervical cancer Hela cells were examined. Cervical cancer specimens were obtained from 47 pre-menopausal patients. The phase of menstrual cycle was determined by case history and HE staining of uterine endometrium. COX-2 was immunohistochemically stained by SABC staining and the staining intensity was determined with computerized image analysis system. Hela cells were incubated with alcohol, E(2), E(2)+MPA, MPA for 12, 24 and 48 h respectively. The expression of COX-2 in Hela cells was detected by Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). Our results showed that the expression of COX-2 was significantly higher during proliferative phase than secretory phase (P0.05). Incubation with E(2) could significantly enhance the expression of COX-2 continually. On the contrary, E(2)+MPA and MPA alone could decrease the expression of COX-2 as compared with the control and E(2) group (P<0.05 and P<0.01 respectively). It is concluded that the expression of COX-2 in cervical cancer of pre-menopausal patients and Hela cells was regulated by estrogen/progestogen.

Protein kinase C modulates telomerase activity in human cervical cancer cells

Telomerase, a ribonucleoprotein reverse transcriptase that extends telomeres of eukaryotic chromosomes is repressed in normal somatic cells but is activated during development and neoplasia. The regulation mechanism of telomerase activity in cancer cells is not clearly known. In this report, a possible affect of PKC on telomerase activity was examined using HeLa and CUMC-6 cervical cancer cell lines. Exposure of cells to PKC inhibitor, bisindolylmaleimide I and Go6976, and high levels of PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA) resulted in the inhibition of PKC activity in both cells. Telomerase activities were also inhibited by bisindolyl-maleimide I and Go6976, respectively, in a time-dependent manner. As PKC activity changes in TPA-treated cervical cancer cells, telomerase activities were increased at low dose of TPA and decreased at high dose. The expression levels of human telomerase subunits, human telomerase RNA (hTR) were not influenced by PKC modulating drugs. In contrast, the expression of full-length human telomerase reverse transcriptase (hTERT) was decreased after exposure to bisindolylmaleimide I and Go6976 in a time-dependent manner. hTERT expression was not affected by low dose of TPA. In contrast, high dose of TPA inhibited hTERT expression level. But the expression patterns of beta-deletion transcript of hTERT after 72 h of treatment with PKC inhibitors or high dose of TPA exposure were not discernable as compared with those of full-length hTERT transcripts to PKC modulating drugs. These results suggest that PKC-modulating drugs altered telomerase activities by affecting full-length hTERT expression profile in human cervical cancers.

Glutathione level and its relation to radiation therapy in patients with cancer of uterine cervix.

Glutathione functions as an important antioxidant in the destruction of hydrogen peroxide and lipid peroxides by providing substrate for the glutathione peroxidase and also promotes the ascorbic acid. Glutathione plays a vital role in detoxification of xenobiotics, carcinogens, free radicals and maintenance of immune functions. The study was aimed to determine plasma glutathione as well as erythrocyte glutathione and glutathione peroxidase in patients with invasive cervical carcinoma (n = 30) before initiation and after completion of radiotherapy and subsequently, at the time of first three monthly follow-up visit. The levels of plasma glutathione, erythrocyte glutathione and glutathione peroxidase activity were found to be lower in all cervical cancer patients as compared to age matched normal control women. The study indicates a change in antioxidant status in relation with the glutathione system among patients with invasive carcinoma of the uterine cervix. This study also demonstrates the effect of radiation therapy on this antioxidant system.

Proteinase-inhibitor activity in sera of patients with carcinoma of the cervix uteri

Se ha demostrado claramente la participación de las proteinasas neoplásicas en la progresión de los cánceres; por otra parte se sabe que el inhibidor más abundante de estas enzimas proteolíticas, el inhibidor alfa-1-proteinasa (IAP) está aumentando en los pacientes con diferentes cánceres. Nosotros y otros investigadores hemos demostrado que apesar del aumento cuantitativo de IAP su función inhibitoria está relativamente disminuida. Nuestro objetivo fue el investigar la actividad inhibitoria del IAP en diferentes estadios del carcinoma de cérvix uterino. Se estudiaron pacientes con displasia cervical, con carcinoma in situ y con carcinoma invasor. El IAP se cuantificó con nefelometría Laser y la capacidad inhibitoria de tripsina (CIT), por el método de Liebermann. Se calculó el indice CIT/IAP y se realizó un estudio estadístico de los valores obtenidos. Las displasias no mostraron diferencias estadísticamente significativas con los testigos; sin embargo, 82% de los pacientes con carcinoma in situ y 87.3% de aquellos con carcinoma invasor mostraron valores IAP arriba de 2 D.S. del promedio. No se encontró ninguna diferencia significativa de los valores del CIT en ninguno de los grupos, pero el índice CIT/IAP disminuyó a 0.54 en el carcinoma in situ y a 0.56 en el carcinoma invasor, lo que indica una reducción de casi 50% de la función inhibitoria de la proteolisis. Estos hallazgos sugieren que la disminución relativa de la actividad antiproteolítica observada puede ser un factor determinante en favor de la progresión neoplásica