Biomedical subjects

Akseli Hemminki

Publications and source records attributed to Akseli Hemminki.

44 records · Page 3Linked to original sources

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↗

PubMed2002

The flt-1 promoter for transcriptional targeting of teratocarcinoma.

Flt-1, a receptor for vascular endothelial growth factor, is known to display dysregulated expression in both tumor vasculature and tumor cells per se, suggesting that the flt-1 promoter might be a useful candidate to achieve tumor-specific transgene expression. In addition, adenoviral vectors containing transgenes under the control of the flt-1 promoter achieve very low levels of expression in the normal liver, the major organ responsible for blood clearance of adenoviruses and inadvertent transgene-related toxicity. Thus, we assessed the ability of adenoviral vectors containing the flt-1 promoter to achieve transgene expression in a range of gynecological and breast tumor lines. High transgene expression levels were detected in teratocarcinoma lines, correlating with levels of flt-1 mRNA. These results suggest that the flt-1 promoter could be useful for transcriptionally targeted gene expression to teratocarcinoma, and that evaluation in other flt-1-positive tumors is warranted.

Animals↗

PubMed2002

Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses.

Adenovirus serotype 5 (Ad5) displays unparalleled gene transfer efficacy to cells with high coxsackie-adenovirus receptor (CAR) expression. Unfortunately, cells isolated from clinical human cancers, both ovarian and other types, express highly variable and often low levels of CAR. Fortunately, native Ad5 tropism can be modified to circumvent CAR deficiency and to enhance infectivity. Ad5/3luc1 incorporates the serotype 3 fiber knob and binds to a receptor distinct from CAR, while the fiber of Ad5lucRGD is modified with an RGD-4C motif, allowing CAR-independent binding to integrins. We studied the liver tropism and blood clearance of these viruses after intravenous (i.v.) injection, and biodistribution after intraperitoneal (i.p.) injection to tumor-bearing mice. To estimate efficacy, we assessed gene transfer to purified human primary ovarian cancer cells, and in a mouse model of ovarian cancer. Ad5/3luc1 achieved improved gene transfer over Ad5lucRGD, and both infectivity-enhanced viruses were superior to the isogenic control with an unmodified Ad5 capsid. In the presence of malignant ascites, gene transfer was improved with both Ad5/3luc1 and Ad5lucRGD. Thus, retargeting to the Ad3 receptor enhances gene transfer to clinically relevant ovarian cancer substrates, while the mouse toxicity and biodistribution profile of both fiber-modified Ad vectors is comparable to Ad5.

Adenoviridae↗

PubMed2002

Adenoviruses in oncology: a viable option?

The feasibility of using adenoviruses for gene therapy has been under close scrutiny recently, as it has become clear that significant toxicity can result from the strong immune response created by intravenous administration of large doses of first generation adenovirus vectors. This suggests that other vectors could be more useful for treatment of metabolic and hereditary disease, where widespread transduction is often necessary for effective gene replacement, and the viability of target cells is important. However, promising recent results in human cancer trials have confirmed that adenoviruses can be very useful in oncology. For cancer treatment, the unparalleled transduction efficacy of adenovirus in dividing and dormant cells is a major benefit. As the goal in cancer gene therapy is to kill infected tumour cells, long-term transgene expression is not necessary. In addition, the immune response generated against infected cells could be useful for eradicating uninfected tumour. Importantly, more than 670 cancer patients have been treated with adenovirus intratumorally, intra-arterially, intraperitoneally and intravenously with very manageable adverse effects and no unexpected severe or lethal toxicity. Currently, the most promising approaches are based on replication-competent agents that allow efficient tumour penetration because of their capacity for tissue-specific replication. In addition to transcriptional control, it is becoming clear that targeting is necessary for efficient tumour transduction and less infection of normal tissues. Exciting results are anticipated when the first selectively replicating targeted adenoviruses go to clinical trials. In conclusion, intense gene therapy and virological research have suggested that while other vectors could be more useful for treatment of hereditary disease, adenoviruses are highly promising and safe agents for oncology, as suggested in a number of early phase clinical trials.

Adenoviridae↗

PubMed2002

Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells.

Gene delivery efficiency in clinical cancer gene therapy trials with recombinant adenoviruses (Ads) based on serotype 5 (Ad5) has been limited partly because of variable expression of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human primary cancer cells. As a means of circumventing CAR deficiency, Ad vectors have been retargeted by creating chimeric fibers possessing knob domains of alternate Ad serotypes. In this study, we have constructed an Ad5-based vector, Ad5/3luc1, with a chimeric fiber protein featuring a knob domain derived from Ad3. This virus is retargeted to the Ad3 receptor and, therefore, has different tissue tropism. A novel knob binding assay was used to measure expression of CAR and the Ad3 receptor. Further, to evaluate the correlation of receptor expression and infectivity by Ad, a panel of ovarian cancer cell lines and purified primary cancer cells were infected with Ad5luc1 and Ad5/3luc1 at 50, 200, and 1000 viral particles/cell. Our results confirm that Ad5/3luc1 is retargeted to the Ad3 receptor. Furthermore, the Ad3 receptor is present at higher levels than CAR on ovarian adenocarcinoma cells. Also, the amount of binding to primary receptor appears to be the major factor determining the efficiency of transgene expression. The Ad5/3 chimera displays enhanced infectivity for ovarian cancer cell lines and purified primary tumor cells, which could translate into increased efficacy in clinical trials.

Adenocarcinoma↗

PubMed2002

Adenoviral gene therapy for cancer: from vectors to targeted and replication competent agents (review).

Gene therapy is an exciting novel approach for treating cancers resistant to currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development, with some promising early results reported with mutation compensation, molecular chemotherapy and replication competent viruses. Adenoviruses are among the most popular vehicles and there is a wealth of clinical data suggesting excellent safety for treatment of cancer patients. Current developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters. Another rapidly developing field is replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Further, infectivity enhancement strategies can overcome variable expression of the primary adenovirus receptor on tumor cells, which may have reduced the clinical efficacy of previous strategies. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and frequently synergistic effects can be observed. Therefore, the first routine clinical applications are likely to be combination treatments.

Adenoviridae↗

PubMed2002

Conditionally replicative adenoviruses for ovarian cancer therapy.

The purpose of this review article is to present a logical rationale for the investigation of conditionally replicative adenoviral vectors for the treatment of ovarian carcinoma. A medline database search was performed to identify relevant articles in the English language for the years 1966 to present. The key words used included replicative adenovirus, conditionally replicative adenovirus, transcriptional targeting, replication selective adenovirus, and "ONYX." A total of 89 references were identified and reviewed. Each reference was reviewed for relevance to clinical translation of conditionally replicative adenoviral vector therapy for ovarian cancer. Data from current clinical trials would suggest that potential obstacles for effective replicative viral therapy of ovarian carcinoma include efficient tumor cell infection, restrictions of the cell surface coxsackie and adenovirus receptor, rapid clearance of vector in the ascites environment, tumor cells specificity, and limitations of current findings of clinical trials. The articles were, therefore, evaluated and included if they addressed these shortcomings. Current data would suggest that advanced generation conditionally replicative adenoviral vectors will soon be available for clinical trials in ovarian cancer. Ovarian cancer, because of expression of targetable receptors, transducible cells, and containment within the i.p. cavity, represents a solid tumor suited uniquely for investigation with advanced generation conditionally replicative adenoviral vectors.

Adenoviridae↗