Aristocratic human papillomavirus drove cervical cancer: a study of the therapeutic potential of the combination of interferon with zinc.

Human papillomavirus (HPV) infection is related to cancer growth of vaginal, cervical, vulva, penile, anogenital, and non-genital oropharyngeal sites. HPV, as a sexually transmitted virus, infects all sexes similarly but with more significant pathological risks in women. This accounts for high mortality due to late detection and poor prognosis. The initial development and eventual progress of this cancer type depend entirely on three main oncogenes E5, E6 and E7, constitutively expressed to lead to carcinogenesis. Despite an opportunity for pharmacological therapy, there is still a shortage of medical treatment that may remove HPV from infected lesions. This study offers a concise summary of the nature of the issue and the current status of work on potential lead molecules and therapeutic approaches that show the capacity of HPV therapies to counteract the roles of deregulation of E5, E6, and E7.

Dose distribution of brachytherapy for locally advanced (stage IIB) cervical cancer.

PURPOSE: The aim of the study was to compare the dose distributions of combined intracavitary and interstitial (IC/IS) brachytherapy with 3-catheter IC brachytherapy in treating locally advanced (stage IIB) cervical cancer. METHODS AND MATERIALS: In total, 46 patients were included, each with stage IIB cervical cancer, local lesion sizes ≥5 cm, and tumors that had not regressed after 45 Gy/25 F external intensity-modulated radiotherapy. To identify the dosimetric advantage of delivering a local boost to high-risk (HR)-cervix in IC/IS, patients were divided into two groups: IC/IS and IC/IS + HR-cervix. The differences in dosimetric parameters were compared between the two groups. Comparisons were then made between the parameters of the four planning methods: IC (Point A), IC (three dimensional [3D]), IC/IS, and IC/IS + HR-cervix. RESULTS: In patients with IC/IS implants, the relative uterine tandem dwell time was significantly extended in the IC/IS + HR-cervix group, and the V150 and V200 volumes of HR-cervix were increased (all p < 0.001), whereas the D90 and D100 values of the IC/IS + HR-cervix group were lower than those in the IC/IS group. In pairwise comparisons, HR-cervix V150 and V200 values were lowest in the IC/IS group, followed by the IC (3D), IC/IS + HR-cervix, and IC (Point A) groups. All differences were statistically significant (p < 0.05), with the exception of IC/IS vs. IC (3D). CONCLUSIONS: When treating locally advanced cervical cancer (stage IIB, local residual volume ≥5 cm after external radiotherapy), the IC/IS + HR-cervix optimization method can meet the HR clinical target volume D90 dose requirement, normal tissue dose limits, and can escalate doses to local areas of the cervix.

Computed Tomography-Guided Interstitial Brachytherapy for Locally Advanced Cervical Cancer: Introduction of the Technique and a Comparison of Dosimetry With Conventional Intracavitary Brachytherapy.

OBJECTIVE: We present a new technique of 3-dimensional computed tomography-guided interstitial (IS) brachytherapy (BT) for locally advanced cervical cancer, offering a more advantageous clinical treatment approach. MATERIALS/METHODS: Interstitial BT was performed using an applicator combining uterine tandem and metal needles; needles were inserted freehand under real-time 3-dimensional computed tomography guidance. Twenty-eight patients with bulky tumors and/or parametrial extension (tumor size > 5 cm) after external beam radiotherapy received IS BT. Dosimetric outcomes of the IS BT including the total dose (external beam radiotherapy and high dose-rate BT) D90 for the high-risk clinical target volume (HR-CTV) and D2cc for the organs at risk (OARs) were investigated and compared with a former patient group consisting of 30 individuals who received the conventional intracavitary (IC) BT. RESULTS: The mean D90 values for HR-CTV in the IC BT and IS BT groups were 76.9 ± 5.7 and 88.1 ± 3.3 Gy, respectively. Moreover, 85.7% of the patients received D90 for HR-CTV of 87 Gy or greater in the IS BT group, and only 6.7% of the patients received D90 for HR-CTV of 87 Gy or greater in the IC BT group. The D2cc for the bladder, rectum, and sigmoid were 84.7 ± 6.8, 69.2 ± 4.2, and 67.8 ± 4.5 Gy in the IC BT group and 81.8 ± 6.5, 66.8 ± 4.0, and 64.8 ± 4.1 Gy in the IS BT group. The mean number of needles was 6.9 ± 1.4, with a mean depth of 2.9 ± 0.9 mm for each IS BT. Interstitial BT was associated with only minor complications. CONCLUSIONS: The IS BT technique resulted in better dose-volume histogram parameters for large volume tumors (>5 cm) compared with the conventional IC BT and acceptable risk of acute complications in locally advanced cervical cancer and is clinically feasible.

Salvage interstitial brachytherapy based on computed tomography for recurrent cervical cancer after radical hysterectomy and adjuvant radiation therapy: case presentations and introduction of the technique.

PURPOSE: Locally recurring cervical cancer after surgery and adjuvant radiotherapy remains a major therapeutic challenge. This paper presents a new therapeutic technique for such patients: interstitial brachytherapy (BT) guided by real-time three-dimensional (3D) computed tomography (CT). MATERIAL AND METHODS: Sixteen patients with recurrent cervical cancer after radical surgery and adjuvant external-beam radiotherapy (EBRT) were included in this study. These patients underwent high-dose-rate (HDR) interstitial BT with free-hand placement of metal needles guided by real-time 3D-CT. Six Gy in 6 fractions were prescribed for the high-risk clinical target volume (HR-CTV). D90 and D100 for HR-CTV of BT, and the cumulative D2cc for the bladder, rectum, and sigmoid, including previous EBRT and present BT were analyzed. Treatment-related complications and 3-month tumor-response rates were investigated. RESULTS: The mean D90 value for HR-CTV was 52.5 ± 3.3 Gy. The cumulative D2cc for the bladder, rectum, and sigmoid were 85.6 ± 5.8, 71.6 ± 6.4, and 69.6 ± 5.9 Gy, respectively. The mean number of needles was 6.1 ± 1.5, with an average depth of 3.5 ± 0.9 cm for each application. Interstitial BT was associated with minor complications and passable tumor-response rate. CONCLUSIONS: Interstitial BT guided by real-time 3D-CT for recurrent cervical cancer results in good dose-volume histogram (DVH) parameters. The current technique may be clinically feasible. However, long-term clinical outcomes should be further investigated.

Clinical feasibility of interstitial brachytherapy using a "hybrid" applicator combining uterine tandem and interstitial metal needles based on CT for locally advanced cervical cancer.

PURPOSE: To explore the dosimetric advantage of target volume and surrounding normal tissue by using interstitial (IS) brachytherapy (BT) based on three-dimensional CT in locally advanced cervical cancer, as a simple and effective clinical treatment approach. METHODS AND MATERIALS: Fifty-two patients with poor tumor response to external beam radiotherapy and a residual tumor >5 cm at the time of the first BT were included. IS BT was performed using a "hybrid" applicator combining uterine tandem and free metal needles based on three-dimensional CT. The high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume, and organs at risk were contoured. The total dose, including external beam radiotherapy (45 Gy in 25 fractions) and high-dose-rate BT (30 Gy in 5 fractions), was biologically normalized to conventional 2-Gy fractions. D90 and D100 for HR-CTV and intermediate-risk clinical target volume and D2cc for the bladder, rectum, and sigmoid were analyzed. RESULTS: The mean D90 value for HR-CTV was 88.4 ± 3.5 Gy. Totally, 88.5% of the patients received D90 for HR-CTV ≥87 Gy. The D2cc for the bladder, rectum, and sigmoid were 81.1 ± 5.6, 65.7 ± 5.1, and 63.1 ± 5.4 Gy, respectively. The mean number of needles was 6.9 ± 1.3 for each application. IS BT was associated with minor complications. CONCLUSION: IS BT using the "hybrid" applicator provides a dosimetric advantage for target volume and organs at risk in large-volume (>5 cm) tumors and is, thereby, clinically feasible. However, the long-term curative effect and possible toxicity need further clinical observation.

Knockdown of Wip1 Enhances Sensitivity to Radiation in HeLa Cells Through Activation of p38 MAPK.

The objectives of the study were to investigate the functional role and potential mechanism of wild-type p53-induced phosphatase (Wip1) in cervical cancer cell line HeLa cells, along with the effect of knockdown of Wip1 in combination with γ-irradiation on the HeLa cells. Expression of Wip1 was silenced or overexpressed. After transfection, cell viability was determined. Moreover, γ-irradiation and SB203580 were performed to explore the effect of colony formation and cell apoptosis. Likewise, protein expression levels of p38, p-p38, p53, and p-p53 were assessed in the presence or not of SB203580 and overexpression of Wip1. Both the mRNA and protein levels of Wip1 were significantly decreased by transfection with Wip1-specific small interfering RNA (siRNA) but were significantly increased by transfection with pcDNA3.1-Wip1. Knockdown of Wip1 significantly decreased cell growth and colony formation ability and increased apoptotic rate. Additionally, better results were obtained by knockdown of Wip1 in combination with γ-irradiation. The protein expression levels of p-p38 (p < 0.05), p53 (p < 0.01), and p-p53 (p < 0.05) were all significantly increased by knockdown of Wip1. However, application of SB203580 reversed the effects. Our study confirms the important roles of Wip1 in cervical cancer. Knockdown of Wip1 enhances sensitivity to radiation in HeLa cells by inhibiting cell proliferation and inducing apoptosis through activation of p38 MAPK.

Caffeine does not enhance radiosensitivity of normal liver tissue in vivo.

The aim of this study was to determine whether caffeine enhanced radiosensitivity of normal liver tissue in a rat radiation-induced liver disease model. Buffalo rat McA-RH7777 hepatocellular cancer cells and BRL3A normal liver cells were irradiated, and cell cycle distribution and apoptosis rates were analyzed. A rat model of radiation-induced liver disease was established, rats were randomized into four groups: control; caffeine alone; irradiation (IR) alone; and caffeine plus IR (Caff + IR) group. Apoptosis rates in normal rat liver tissue after IR were evaluated by TUNEL staining and caspase-3 Western blot. Transaminase activity was measured and histopathological examination was done after IR. Caffeine abrogated IR-induced G2 phase arrest (Caff + IR vs. IR: 40.9 ± 4.0 vs. 60.7 ± 5.5%, at 12 h after IR) and increased apoptosis rates (Caff + IR vs. IR: 56.1 ± 6.8 vs. 35.5 ± 4.0%, at 72 h after IR) in McA-RH7777 cells, but did not affect IR-induced G2 phase arrest and apoptosis rates at any time point after IR in BRL3A cells. Caffeine did not enhance apoptosis, transaminase activity, or histopathological injury of normal rat liver tissue at any time points after IR. This study suggests that caffeine might not enhance radiosensitivity of normal liver tissue in vivo. In an earlier study, we reported that caffeine enhanced radiosensitivity of human hepatocellular cancer in a nude mice model. Together, these results offer feasibility of clinical application.

Radiation-induced liver fibrosis is mitigated by gene therapy inhibiting transforming growth factor-ß signaling in the rat.

PURPOSE: We determined whether anti-transforming growth factor-ß (TGF-ß) intervention could halt the progression of established radiation-induced liver fibrosis (RILF). METHODS AND MATERIALS: A replication-defective adenoviral vector expressing the extracellular portion of human TßRII and the Fc portion of immunoglobulin G fusion protein (AdTßRIIFc) was produced. The entire rat liver was exposed to 30 Gy irradiation to generate a RILF model (RILFM). Then, RILFM animals were treated with AdTßRIIFc (1 × 10(11) plaque-forming units [PFU] of TßRII), control virus (1 × 10(11) PFU of AdGFP), or saline. Delayed radiation liver injury was assessed by histology and immunohistochemistry. Chronic oxidative stress damage, hepatic stellate cell activation, and hepatocyte regeneration were also analyzed. RESULTS: In rats infected with AdTßRIIFc, fibrosis was significantly improved compared with rats treated with AdGFP or saline, as assessed by histology, hydroxyproline content, and serum level of hyaluronic acid. Compared with AdGFP rats, AdTßRIIFc-treated rats exhibited decreased oxidative stress damage and hepatic stellate cell activation and preserved liver function. CONCLUSIONS: Our results demonstrate that TGF-ß plays a critical role in the progression of liver fibrosis and suggest that anti-TGF-ß intervention is feasible and ameliorates established liver fibrosis. In addition, chronic oxidative stress may be involved in the progression of RILF.

Caffeine enhances radiosensitization to orthotopic transplant LM3 hepatocellular carcinoma in vivo.

The aim of this study was to determine whether caffeine enhanced radiosensitization in an orthotopic transplant of LM3 human hepatocellular cancer in nude mice. LM3 hepatocellular carcinoma cells were infected with red fluorescent protein and irradiated, and cell cycle distribution and survival fraction were detected. A nude mouse model of orthotopic transplant of red fluorescent protein-expressing LM3 hepatocellular cancer was established. Nude mice were divided into four groups: control (NS); caffeine (Caff) alone; irradiation (IR) alone; and caffeine + IR (Caff + IR). Tumor growth curves were described. Expression of cyclin and apoptosis were evaluated by analysis of phosphorylated cyclin dependent kinase 1 (CDC2) Tyr15 (CDC2-Tyr15-P), cyclinB1, TUNEL staining, and caspase-3. Caffeine abrogated IR-induced G(2) phase arrest and decreased survival of irradiated LM3 cells. Caffeine enhanced radiosensitivity of LM3 hepatocellular cancer in vivo. Tumor growth delay time in the Caff + IR group was 14.3 days compared with the NS group, 14.1 days compared with the Caff alone group, and 7.2 days compared with the IR alone group. At 15 Gy, expression of CDC2-Tyr15-P in the Caff + IR group (26.0 +/- 8.9%) was significantly lower than in the IR alone group (68.4 +/- 10.6%), expression of cyclinB1 and proportion of TUNEL-positive cells in the Caff + IR group (30.4 +/- 8.7% and 59.2 +/- 9.5%, respectively) was significantly higher than in the IR alone group (7.0 +/- 3.7% and 24.2 +/- 7.2%, respectively), expression of caspase-3 was consistent with the TUNEL staining results. This study suggested that caffeine might enhance the radiosensitivity of LM3 hepatocellular cancer in vivo, and may be feasible for further clinical applications.

Regenerative capacity of normal and irradiated liver following partial hepatectomy in rats.

PURPOSE: To investigate the regenerative capacity and proliferation related to cell cycle modulators in irradiated livers after partial hepatectomy (PH) in rats. METHODS AND MATERIALS: Two experimental groups were given a single dose of either 4-Gy or 8-Gy photon radiation to the whole liver following PH. The control group underwent only PH, without irradiation. The liver specimens were analysed for apoptosis, proliferation and cell cycle related genes between 0.5 and 12 days. RESULTS: Mean change in weight of the remnant liver in the 8-Gy group was significantly lower than in the control and 4-Gy groups. The apex of proliferating cell nuclear antigen labelling and bromodeoxyuridine incorporation index in two irradiated groups were also apparently lower than that in control group. After PH, transforming growth factor beta-1 (TGFbeta1), and the type II receptor of TGFbeta (TGFbetaR-II), anti-tumour protein 53(p53) and anti-tumour protein21(p21) protein expression in the irradiated livers was higher than in unirradiated ones. Significant apoptosis was noted in 8-Gy group. However, the maximal value of hepatocyte growth factor (HGF) mRNA and protein expression in the irradiated group was suppressed and restoration of liver function was delayed. CONCLUSION: Whole liver lower dose irradiation can attenuate regenerative capacity following partial hepatectomy in rats.