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October 19, 2006

Scientists Say Genetically-Engineered Form Of Adenovirus Targets Cancer Cells

Topics: Medical Science News

F5_flat_b.jpgThe use of oncolytic adenoviruses as cancer gene therapy has been limited by their uneven penetration and distribution in tumors. South Korean scientists at Yonsei University studied whether the expression of the cell matrix-degradative protein relaxin by adenovirus could improve adenovirus distribution and penetration in tumors, and now report the development of a a new genetically altered strain of adenovirus (a virus that normally causes colds) that is highly efficient in targeting and killing cancer cells. The adenovirus was implanted with a human gene that is related to the production of relaxin, a hormone associated with pregnancy. The researchers say that when the new adenovirus is injected into cancerous tumours, cancer cells are quickly targeted and killed - leaving normal cells unharmed. Existing viral treatments fail to kill off all the cancerous cells.

"I believe we have found a way to overcome one of the great obstacles to finding a genetically altered viral cure for cancer," Yun Chae-Ok, one of the researchers, told AFP on Thursday.

Following three rounds of injections, more than 90 percent of cancer cells in the brains, liver, lungs and womb of mice disappeared within 60 days, the team said.

As reported in J Natl Cancer Inst. 2006 Oct 18;98(20):1482-93, entitled "Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy, the scientists generated relaxin-expressing, replication-incompetent (dl-lacZ-RLX) and -competent (Ad-DeltaE1B-RLX) adenoviruses by inserting a relaxin gene into the E3 adenoviral region:
Controls were parental adenoviruses (dl-lacZ and Ad-DeltaE1B) and phosphate-buffered saline (PBS) (vehicle). Replication-incompetent viruses, which do not lyse cells, were used to assess transduction efficiency. Viral spread in tumor spheroids, made by dissecting tumor tissue into homogeneous fragments, was assessed by reporter gene (i.e., lacZ) expression. Tumor growth inhibition was assessed by injecting adenoviruses into xenograft tumors in athymic mice (n = 8 or 9). Overall survival was assessed by the Kaplan-Meier method. Extracellular matrix was examined with Masson's trichrome staining. Therapeutic efficacy was evaluated by assessing spontaneous pulmonary metastasis in the B16BL6 melanoma mouse model and growth inhibition of orthotopically implanted hepatoma (n = 4-6). All statistical tests were two-sided.

In tumor spheroids and established solid tumors in vivo, transduction with dl-lacZ-RLX, compared with parental virus or vehicle, elicited higher transduction efficiency and viral spread throughout the tumor mass. Infection with Ad-DeltaE1B-RLX, compared with parental virus, elicited greater viral persistence and spread, leading to increased survival (e.g., 100%, 95% confidence interval [CI] = 63.1% to 100%, for C33A tumor-bearing mice treated with Ad-DeltaE1B-RLX, and 50%, 95% CI = 15.7% to 84.3%, for C33A tumor-bearing mice treated with Ad-DeltaE1B). Infection with Ad-DeltaE1B-RLX substantially decreased the collagen content of tumor tissue but not of adjacent normal tissue, compared with noninfected tissues. Intratumoral injection of Ad-DeltaE1B-RLX inhibited the formation of lung metastases in mice (PBS = 268 mg of metastatic tumor per mouse and Ad-DeltaE1B-RLX = 10 mg; difference = 258 mg, 95% CI = 94 to 426; P = .003, Mann-Whitney test). Systemic treatment with Ad-DeltaE1B-RLX completely inhibited the growth of Hep1 hepatocellular carcinomas (PBS = 20.2 mg of tumor per mouse and Ad-DeltaE1B-RLX = 0 mg; difference = 20.2 mg, 95% CI = 3.7 to 36.7; P = .004, Mann-Whitney test).
The researchers concluded that extracellular matrix degradation by relaxin expressed by adenoviruses increased viral distribution and tumor penetration, inhibited tumor growth and metastasis, and increased the survival of mice.

The researchers anticipate clinical tests to be carried out early in 2007 and last 18 months.

Posted by Richard at October 19, 2006 11:47 AM

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