PubMed Health⌕ Search

Biomedical subjects

Ronald D Alvarez

Publications and source records attributed to Ronald D Alvarez.

At least 55 records · Page 3Linked to original sources
PubMed2004

Immunohistochemical evaluation of the c-kit proto-oncogene in sarcomas of the uterus: a case series.

OBJECTIVE: To evaluate the incidence of c-kit expression in uterine sarcomas. STUDY DESIGN: Immunohistochemical evaluation for expression of c-kit was performed on specimens from 11 patients with pathologically documented uterine sarcomas. Histologic subtypes included 5 carcinosarcomas, 3 leiomyosarcomas and 3 endometrial stromal sarcomas. Histologic sections of formalin-fixed, paraffin-embedded hysterectomy specimens from patients with uterine sarcomas were immunostained with c-kit (CD117) antibody. Overall staining intensity was graded as strong, intermediate or weak. RESULTS: In all 11 patients with uterine sarcoma, c-kit immunostaining was positive. Four specimens demonstrated stronger staining intensity than did the gastrointestinal stromal tumor control. Five specimens demonstrated intermediate staining intensity. Two specimens demonstrated weak staining intensity. Furthermore, in the carcinosarcoma specimens both the epithelial and sarcomatous elements were positive for c-kit staining. CONCLUSION: In this case series, c-kit expression was demonstrated in all sarcomas of the uterus regardless of histologic type. These results suggest that such drugs as imatinib mesylate, which inhibit the c-kit tyrosine kinase, should be investigated for these mesenchymal neoplasms.

Biomarkers, Tumor↗
PubMed2003

Cervical cancer chemoprevention, vaccines, and surrogate endpoint biomarkers.

At the Second International Conference on Cervical Cancer, held April 11-14, 2002, experts in cervical cancer prevention, detection, and treatment reviewed the need for more research in chemoprevention, including prophylactic and therapeutic vaccines, immunomodulators, peptides, and surrogate endpoint biomarkers. Investigators and clinicians noted the need for more rigorous Phase I randomized clinical trials, more attention to the risk factors that can affect study results in this patient population, and validation of optical technologies that will provide valuable quantitative information in real time regarding disease regression and progression. They discussed the role of the human papillomavirus (HPV) in cervical cancer development and the importance of developing strategies to suppress HPV persistence and progression. Results in Phase I randomized clinical trials have been disappointing because few have demonstrated statistically significant regression attributable to the agent tested. Researchers recommended using a transgenic mouse model to test and validate new compounds, initiating vaccine and immunomodulator trials, and developing immunologic surrogate endpoint biomarkers.

Biomarkers, Tumor↗
PubMed2003

Intraperitoneal radioactive phosphorus (32P) versus observation after negative second-look laparotomy for stage III ovarian carcinoma: a randomized trial of the Gynecologic Oncology Group.

PURPOSE: The objectives of this prospective randomized study of consolidation therapy were to evaluate recurrence-free survival (RFS), overall survival (OS), and the morbidity of intraperitoneal (IP) chromic phosphate suspension (32P) therapy in patients with stage III epithelial ovarian carcinoma who have no detectable evidence of disease at the second-look laparotomy (SLL) procedure after primary chemotherapy. PATIENTS AND METHODS: In a multi-institution clinical cooperative trial, 202 eligible patients with a negative SLL were randomly selected to receive either 15 mCi IP 32P (n = 104) or no further therapy (NFT; n = 98). RESULTS: With a median follow-up of 63 months in living patients, 68 patients in the IP 32P group (65%) and 63 patients in the NFT group (64%) have developed tumor recurrence. The relative risk of recurrence is 0.90 (IP 32P to NFT) (90% confidence interval [CI], 0.68 to 1.19). The 5-year RFS rate is 42% and 36% for the IP 32P and NFT groups, respectively; the difference is not statistically significant (log-rank test, P =.27). There was no statistically significant difference in OS (P =.19). The relative risk of death is 0.85 (IP 32P to NFT) (90% CI, 0.62 to 1.16). Sixteen patients (8%) experienced grade 3 or 4 adverse effects, with eight in each respective group. CONCLUSION: Intraperitoneal chromic phosphate did not decrease the risk of relapse or improve survival for patients with stage III epithelial ovarian cancer after a negative SLL. Despite complete pathologic remission at SLL after initial surgery and platinum-based chemotherapy, 61% of stage III ovarian cancer patients had tumor recurrence within 5 years of negative SLL. This indicates a need for more effective initial therapy and further studies of consolidation therapy.

Adult↗
PubMed2003

Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial.

PURPOSE: To determine whether continuing paclitaxel for an extended time period in women with advanced ovarian cancer who had achieved a clinically defined complete response to a platinum/paclitaxel-based chemotherapy could prolong subsequent progression-free survival (PFS) and affect ultimate survival. PATIENTS AND METHODS: Patients were randomly assigned to either three or 12 cycles of single-agent paclitaxel administered every 28 days and were then followed up for progression-free and overall survival. RESULTS: As of September 6, 2001, 277 patients (262 assessable) had entered the trial, with a total of 54 PFS events having developed among 222 patients with follow-up data. With the exception of peripheral neuropathy, there were no major differences in toxicity between the regimens. The median PFS was 21 and 28 months in the three-cycle and 12-cycle paclitaxel arms, respectively. One-sided P values from an unadjusted log-rank test and an adjusted Cox model analysis (for stratification factors) were.0035 and.0023, respectively, both in favor of the 12-cycle arm. The Cox model-adjusted three-cycle versus the 12-cycle progression hazard ratio was estimated to be 2.31 (99% confidence interval, 1.08 to 4.94). With a protocol-specified early termination boundary of P =.005, these findings led the Southwest Oncology Group Data Safety Monitoring Committee to discontinue the trial. As of the date of study closure, there was no difference in overall survival between the treatment arms. CONCLUSION: Twelve cycles of single-agent paclitaxel administered to women with advanced ovarian cancer who attain a clinically defined complete response to initial platinum/paclitaxel-based chemotherapy significantly prolongs the duration of PFS.

Aged↗
PubMed2003

Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity.

Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-gamma. T cells conditioned with the B7-H1-blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.

Animals↗
PubMed2003

Modulation of coxsackie-adenovirus receptor expression for increased adenoviral transgene expression.

An important determinant of gene transfer efficacy with adenoviral vectors is expression of the primary receptor, the coxsackie-adenovirus receptor. Unfortunately, expression may often be low in advanced clinical cancers, including ovarian, colorectal, lung, prostate, and breast cancer. In this study we investigated the feasibility of increasing transgene expression by incubating ovarian cancer cells with various agents and then performing transgene expression analysis. Fluorescence-activated cell sorting and quantitative reverse transcription-PCR were subsequently performed for correlation with receptor and mRNA up-regulation. Furthermore, the results were confirmed in purified clinical ovarian cancer specimens. Possible clinical application was tested using i.p. administration in an orthotopic ovarian cancer animal model. This approach could be useful for increasing adenoviral transgene expression in the context of clinical trials.

Adenoviridae↗
PubMed2003

The secretory leukoprotease inhibitor (SLPI) promoter for ovarian cancer gene therapy.

BACKGROUND: Adenoviruses allow efficient transduction of dividing and non-dividing cells and their safety for the treatment of cancer has been established in clinical trials. However, one disadvantage is their promiscuous tropism. In this regard, tissue-specific promoters (TSPs) could be useful for directing transgene expression to target tissues and for reducing adverse effects in non-target tissues. We hypothesize that selective adenovirus-mediated transgene expression could be achieved through the use of the secretory leukoprotease inhibitor (SLPI) promoter in the context of ovarian cancer. METHODS: Adenoviruses containing the SLPI promoter driving reporter and suicide gene expression were created and tested in ovarian cancer cell lines and primary tumor cells isolated from patients. To evaluate the in vivo activation of the SLPI promoter in comparison to a ubiquitous promoter, intraperitoneal delivery was performed in tumor-bearing mice, followed by analysis of survival or gene expression in normal organs and tumor. RESULTS: The SLPI promoter retained its fidelity in an adenoviral context and was activated in both cell lines and primary cancer cells. The SLPI promoter was induced to a high degree in ovarian cancer cells while showing significantly reduced activity in normal tissues. The therapeutic efficacy of SLPI promoter-controlled gene expression was similar to the ubiquitous promoter in vitro and in an orthotopic murine model of peritoneally disseminated ovarian cancer, with higher activity than controls. CONCLUSIONS: The SLPI promoter is a potentially useful TSP for ovarian cancer and facilitates further development of targeting strategies for improved gene therapy of ovarian carcinomas.

Adenocarcinoma↗
PubMed2003

Complications of indwelling venous access devices in patients with gynecologic malignancies.

OBJECTIVE: The purpose of this study was to evaluate the complication rates associated with indwelling venous access devices in patients with gynecologic malignancies. METHODS: Following IRB approval, a computerized database identified women that had indwelling access devices placed for chemotherapy from March 1999 to June 2001. A retrospective chart review identified 116 venous access devices that were placed in 104 patients. All devices were silicone and had a closed tip design with a three-position valve. Data were collected on patient demographics, clinicopathologic features, type of venous device, and complications. The chi(2) test was used for statistical analysis. RESULTS: Of the 104 patients, 79 had ovarian cancer, 11 had uterine cancer, 10 had cervical cancer, 2 had fallopian tube cancer, and 2 had vaginal cancer. The median age was 61 years. There were a total of 116 venous devices placed: 65 external catheters (EC) and 51 subcutaneous ports (SP). Seventy-nine percent of the patients were administered low-dose coumadin (1 mg/day) for catheter clot prophylaxis. There were three operative complications in the EC group and two in the SP group (P = NS). The most common postoperative complications were infection and thrombosis. Nineteen patients in the EC group experienced a catheter-related infection versus 5 in the SP group (P = 0.025). In the EC group, there were 11 cases of site infection and 8 cases of line sepsis. In contrast, there were 3 cases of exit site infection and 2 cases of line sepsis in the SP group. Deep vein thrombosis occurred in 5 patients with EC and 3 patients with SP (P = NS). Twenty-seven patients with EC had the device removed for catheter-related complications versus 2 patients with SP (P = 0.001). Six patients inadvertently removed their EC. CONCLUSION: There is a significantly higher postoperative complication rate in gynecologic oncology patients with external catheters versus subcutaneous ports. Infection and catheter-related malfunction are more common in patients with external catheters. We recommend the use of subcutaneous ports in the majority of patients with gynecologic malignancies.

Adult↗
PubMed2003

Uterine papillary serous carcinoma: comparisons of outcomes in surgical Stage I patients with and without adjuvant therapy.

OBJECTIVE: Our aim was to determine the outcomes of Stage I uterine papillary serous carcinoma (UPSC) patients with and without adjuvant therapy after comprehensive surgical staging. METHODS: Patients with FIGO Stage I UPSC diagnosed from 1987 to 2000 were identified from tumor registry databases at four institutions. A retrospective chart review identified 60 women who underwent comprehensive surgical staging, including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic/para-aortic lymphadenectomy, and peritoneal cytology. Fisher's exact, chi(2), and log-rank tests were used for the statistical analyses. RESULTS: Of the 60 Stage I patients, 40 (66%) patients received no adjuvant therapy, 12 (20%) received adjuvant radiation therapy (XRT), 7 (12%) received adjuvant chemotherapy (CHM), and 1 (2%) received both XRT and CHM. There were seven recurrences in the observation group versus two recurrences in the XRT group (17% vs 16%, P = 0.9). No recurrences or deaths were observed in the CHM group. The mean disease-free survival rates for the observation and the XRT groups were 31 and 41 months, respectively. The mean overall survival rates for the observation and XRT groups were 39 and 40 months, respectively. The 5-year disease-free survival rates for the observation and XRT groups were 65 and 60%, respectively; the 5-year overall survival rates for observation and XRT groups were 66 and 59%. There was no statistical difference in overall survival among the three groups. CONCLUSION: In this largest reported series of surgical Stage I UPSC patients, recurrence rates were lower than those published in previous studies, suggesting a potential benefit of comprehensive surgical staging in these patients. The risk of recurrence and the mean overall survival were similar between surgical Stage I UPSC patients who were managed conservatively and those treated with adjuvant radiation therapy. These data question the benefit of radiation therapy in UPSC patients with disease confined to the uterus. Finally, given the absence of recurrences and disease-related deaths for adjuvant chemotherapy in these patients, a Phase II/III trial evaluating adjuvant chemotherapy in surgical Stage I UPSC patients should be considered.

Aged↗
PubMed2003

Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy.

OBJECTIVE: The goal of this study was to determine the outcomes of stage IC endometrial carcinoma patients who are managed with and without adjuvant radiation therapy after comprehensive surgical staging. METHODS: Patients with FIGO stage IC adenocarcinoma of the endometrium diagnosed from 1988 to 1999 were identified from tumor registry databases at four institutions. A retrospective chart review identified 220 women who underwent comprehensive surgical staging including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymphadenectomy, and peritoneal cytology. RESULTS: Of the 220 stage IC patients, 56 (25%) patients received adjuvant brachytherapy (BT), 19 (9%) received whole-pelvis radiation (WPRT), and 24 (11%) received both WPRT and BT. One hundred twenty-one patients (55%) did not receive adjuvant radiation. There were 6 recurrences (6%) in the radiated group and 14 (12%) in the observation group (P = 0.20). Seven of fourteen recurrences in the observation group were local, and all local recurrences were salvaged with radiation therapy. Two of seven distant recurrences in this group were also salvaged with surgery and chemotherapy. The overall salvage rate for the observation group was 64%. There was a statistical difference in 5-year disease-free survival between the radiated and observation groups (93% vs 75%, P = 0.013). However, the 5-year overall survival was similar in the two groups (92% vs 90%, P = 0.717). CONCLUSION: Adjuvant radiation therapy improves disease-free survival in surgical stage IC patients; however, overall survival is not improved with adjuvant radiation therapy since the majority of local recurrences in conservatively managed patients can be salvaged with radiation therapy.

Adenocarcinoma↗
PubMed2003

Gene therapy for ovarian cancer: progress and potential.

Gene therapy remains a promising therapeutic modality for ovarian cancer. Yet much work remains to be done to see gene therapy realize its full potential in elucidating the complex genetic interactions of delivered genes within target cancer cells and in the development of improved vector systems. Because most neoplasms involve multiple mutations, the targeting of a single mutation is unlikely to achieve total tumor control: gene therapy strategies that target multiple cellular processes or invoke various antitumor approaches need to be investigated. Additionally, current vector systems do not transduce ovarian cancer cells efficiently and are hampered by immune responses that further limit their efficacy. Additionally, limitations in vector specificity lead to transduction of normal cells and subsequent toxicity. Investigators are developing refinements to current gene therapy approaches that would address these limitations and that are soon to be incorporated into clinical trials. It is hoped that these advances will lead to improvements in the therapeutic index for ovarian cancer gene therapy and provide another effective therapeutic tool for this deadly disease.

Animals↗
PubMed2003

Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus.

Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.

Adenoviridae↗
PubMed2003

Replication of an integrin targeted conditionally replicating adenovirus on primary ovarian cancer spheroids.

Replication competent viruses hold promise for treatment of advanced cancers resistant to available therapeutic modalities. Although preliminary clinical results have substantiated their efficacy, preclinical development of these novel approaches is limited by assay substrates. The evaluation of candidate agents could be confounded by differences between primary tumor cells and tumor cell lines, as discordance in the levels of surface receptors relevant for viral entry has been reported. Since primary tumor cells are difficult to analyze ex vivo for longitudinal observation of virus replication, we developed three-dimensional aggregates or spheroids of unpassaged and purified ovarian cancer cells as a means for prolonging primary tumor cell viability and as a three-dimensional in vitro model for replicative viral infection. Ovarian cancer cells purified from ascites samples were sustained for 30 days while retaining the infection profile with tropism modified and unmodified adenoviruses (Ads). Cell line and primary cell spheroids were used to quantitate the replication and oncolytic potency of replicative Ads in preclinical testing for human ovarian cancer trials. Therefore, spheroids provide a method to sustain purified unpassaged primary ovarian cancer cells for extended periods and to allow evaluation of replicative viruses in a three-dimensional model.

Adenoviridae↗
PubMed2003

The efficacy of 9-cis-retinoic acid (aliretinoin) as a chemopreventive agent for cervical dysplasia: results of a randomized double-blind clinical trial.

9-Cis-retinoic acid (aliretinoin) is a pan-retinoid receptor agonist and has been demonstrated in preclinical models to have potent chemoprevention effects. The purpose of this study was to determine the utility of using aliretinoin as a chemoprevention agent in cervical dysplasia. Patients with histological evidence of cervical intraepithelial neoplasia (CIN) 2/3 were randomized in a double-blind manner to receive high-dose aliretinoin (50 mg), low-dose of aliretinoin (25 mg), or placebo daily for 12 weeks. Compliance and side effects were monitored at various time points during therapy. At the completion of therapy, all of the patients underwent a loop procedure. Histology of pretreatment biopsies was compared with that of loop specimens. One-hundred and fourteen patients with CIN 2/3 were enrolled in the study. In the 112 patients evaluable for toxicity, headache was the most common clinical side effect and was experienced more frequently (74%) in the high-dose aliretinoin group. Eight patients withdrew from the study before completion of study medication because of unacceptable side effects. In the 104 patients evaluable for efficacy, there was no statistical difference in the rate of regression among the placebo (32%), the low-dose aliretinoin (32%), and the high-dose aliretinoin (36%) groups. (P = not significant; power 0.06). Aliretinoin at these dosages and this schedule does not appear to result in significant regression rates in CIN 2/3 patients when compared with placebo. Headache is encountered frequently and may thwart efforts to increase the dose or duration of aliretinoin in future cervical cancer chemoprevention studies. The rate of histological regression in biopsied CIN 2/3 patients is high even over a short time interval, and emphasizes the importance of having a placebo arm and an adequate sample size in cervical dysplasia chemoprevention studies.

Adolescent↗
PubMed2003

Intravenous delivery of adenovirus-mediated soluble FLT-1 results in liver toxicity.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent angiogenic agent and plays a major role in tumor growth and metastases. We have previously reported the locoregional (i.p.) delivery of adenovirus-mediated antiangiogenic soluble FLT-1 (sFLT-1; a naturally encoded potent VEGF antagonist) gene therapy to inhibit VEGF action in a murine ovarian carcinoma model. This study was predicated on the fact that systemic delivery of sFLT-1 might allow an approach for therapy of disseminated tumor. The purpose of this study is to test the effects of i.v. delivered, adenovirus-mediated sFLT-1 on the survival duration in a murine ovarian tumor model and to evaluate the safety of i.v.-delivered versus i.p.-delivered adenovirus-mediated sFLT-1 in non-tumor-bearing mice. EXPERIMENTAL DESIGN: To determine the effects of i.v.-administered adenovirus-mediated sFLT-1 on survival duration of mice bearing i.p. human ovarian tumors, an E1A/B-deleted, (replication-deficient) infectivity-enhanced recombinant adenovirus AdRGDGFPsFLT-1 encoding cDNA for both sFLT-1 and GFP (green fluorescent protein), a control adenovirus AdRGDGFP encoding GFP alone, or PBS was delivered i.v. The therapeutic effect of sFLT-1 was evaluated by survival duration of the mice. Furthermore, the safety of i.v.- or i.p.-delivered adenovirus-mediated sFLT-1 was evaluated by administering AdRGDGFPsFLT-1, AdRGDGFP, or PBS either i.v. or i.p. into non-tumor-bearing mice. Adenovirus-mediated gene expression was determined by determining GFP expression using fluorescent microscopy and by assessing sFLT-1 expression in liver, lungs, spleen, and kidneys by immunohistochemistry using anti-FLT-1 monoclonal antibody. Systemic levels of sFLT-1 were evaluated by ELISA and the toxicity was evaluated by histopathology. RESULTS: The i.v. delivery of AdRGDGFPsFLT-1 in the ovarian tumor model resulted in a shorter duration of survival of the mice as compared with the control group. Furthermore, in the safety evaluation experiment, i.v. administration of AdRGDGFPsFLT-1 in non-tumor-bearing mice principally localized to the liver. This localization lead to sFLT-1 overexpression, mainly in the liver, resulting in hemorrhage and tissue toxicity. However, i.p. delivery of AdRGDGFPsFLT-1 did not localize principally to the liver, leading to negligible expression of sFLT-1, and no intrahepatic hemorrhage or toxicity was observed. The i.v. delivery of the control virus AdRGDGFP also principally localized to the liver, leading to GFP expression mainly in the liver. However, neither hemorrhage nor morphological cytotoxicity was observed. i.p. delivery of AdRGDGFP resulted in ectopic localization to the liver with very little GFP expression and no toxicity. These results suggest that overexpression of sFLT-1 in the liver as a result of i.v. delivery is hepatotoxic. CONCLUSIONS: Our results suggest that i.v. delivery of the sFLT-1 gene via replication-deficient, infectivity-enhanced recombinant adenoviral vectors will result in overexpression of sFLT-1 in the liver leading to unacceptable hepatotoxicity. Tumor-specific targeting of the vectors and tumor-specific expression strategies should be used to ensure a clinically useful antiangiogenesis gene therapy.

Adenoviridae↗
PubMed2002

In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus.

BACKGROUND: Adenovirus-based gene therapy is a promising approach to treat advanced cancers that are resistant to other treatments. However, many primary cells lack the requisite coxsackie-adenovirus receptor (CAR), limiting the in vivo efficacy of gene therapy. Recently, a modified adenovirus that is not dependent on CAR expression for infectivity was developed. We used noninvasive imaging to investigate the in vivo antitumor efficacy of gene therapy using this adenovirus in an animal model of ovarian cancer. METHODS: The adenoviral vectors RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes simplex virus thymidine kinase (TK) for molecular chemotherapy and the human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were established from highly aggressive SKOV3.ip1 cells in immune-deficient mice. Adenoviral constructs were infected intratumorally or intraperitoneally once a day for 3 days. Control mice received three injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector that includes a luciferase marker gene. The somatostatin analogue (99m)Tc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that was injected into subcutaneous tumors. For mice with peritoneal tumors, survival was compared among the different treatment groups using Kaplan-Meier analysis with the log-rank statistic. All statistical tests were two-sided. RESULTS: Tumor-associated RGDTKSSTR could be detected 15 days after introduction of the vector. In the subcutaneous model, tumors injected with RGDTKSSTR were statistically significantly smaller than those injected with AdTKSSTR (P<.001). In the intraperitoneal model, mice treated with RGDTKSSTR lived longer (survival at day 45 = 63.6%; 95% confidence interval [CI] = 35.2% to 92.0%) than those treated with AdTKSSTR (survival at day 45 = 0%) or Ad5Luc1 (survival at day 45 = 18.1%; 95% CI = 0.0% to 41.0%). DISCUSSION: RGDTKSSTR shows antitumor efficacy against ovarian cancer in vivo in animal models. The virus can be imaged noninvasively and may have the potential to be a useful agent for treating ovarian cancer.

Adenoviridae↗
PubMed2002

Treatment of ovarian cancer with a tropism modified oncolytic adenovirus.

Ad5-Delta 24RGD is an adenovirus that is selectively replication competent in cells defective in the Rb/p16 pathway, such as ovarian cancer cells. The fiber of Ad5-Delta 24RGD contains an integrin binding RGD-4C motif, allowing Coxsackie adenovirus receptor-independent infection of cancer cells. Oncolysis of cell lines was similar to that of a wild-type control, and replication in primary tumor material was shown using a novel three-dimensional spheroid model. Finally, an orthotopic murine model of peritoneally disseminated ovarian cancer was used to test i.p. administration to tumor-bearing animals. Injection of the agent resulted in eradication of i.p. disease, whereas control animals expired (P < 0.0001). These results suggest that Ad5-Delta 24RGD could be useful for treatment of ovarian cancer in humans.

Adenoviridae↗