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Adenovirus Delivers Replacement p53 Gene Into Tumors

Adenovirus Delivers Replacement p53 Gene Into Tumors

NEW ORLEANS--An altered adenovirus successfully delivered a normal p53 tumor-suppressor gene to several kinds of tumors, Jo Ann Horowitz, MD, clinical project director for Oncology Clinical Research, Schering-Plough Research Institute, Kenilworth, NJ, reported at the annual meeting of the American Association for Cancer Research.

When a cell has a functioning p53 gene, it produces the p53 protein, which suppresses the formation of tumors. A mutation in this crucial gene can allow many types of tumors to grow. If a normal p53 gene could be introduced into a tumor cell to replace the malfunctioning one, the cancer cell might be induced to go through apoptosis.

Testing this theory involves finding a good way to deliver p53 genes into as many tumor cells as possible. The Schering-Plough researchers tested a modified adenovirus. Adenoviruses easily infect human cells under natural conditions and seem good prospects for gene therapy vectors. The particular adenovirus used in these studies was SCH 58500, an adenovirus with two important alterations: It cannot replicate (and so should not cause an infection in the patient), and it contains a cloned human wild-type (or normal) p53 gene.

In five pilot phase I studies, the researchers gave a single dose of SCH 58500 to 74 patients. Patients with colon cancer metastatic to the liver received their dose in the intrahepatic artery (IHA); patients with ovarian carcinomatosis received their dose intraperitoneally (IP); and patients with melanoma, breast, head and neck, or non-small-cell lung cancer received the dose directly into the tumor.

Several dose levels were tested, with at least three patients assigned to each dose level. All patients were required to have antibodies to the adenovirus before the start of the study.

The objectives of the pilot program, Dr. Horowitz said, were to assess safety by level and route of administration, assess biologic activity using an RT-PCR [reverse transcriptase-polymerase chain reaction] assay in tumor as well as normal tissue, and to assess the impact of the antiadenoviral antibody on the ability to express the transgene.

Normal p53 Was Expressed

Afterwards, the tumors were tested to see whether the normal p53 gene was expressed. Most tumors did show expression, with higher doses of SCH 58500 more likely to result in expression. "We did think we saw a threshold for transient expression at about 7.5 × 1011 particle dose," Dr. Horowitz said. "The presence of antiadenoviral antibodies at baseline and in subsequent cycles did not preclude transgene expression."

Later, the researchers made some changes to the protocols. They allowed patients who did not have antibodies to adenoviruses to take part, and they tested administering the daily dose in several parts.

"SCH 58500 has a very acceptable safety profile," Dr. Horowitz said. "Our dosages for further investigation, to be given as multiple daily doses, are: by the intratumoral route, 7.5 × 1012 particles; by the IHA route, 2.5 × 1013 particles; and by the IP route, 7.5 × 1013 particles. These may be given in combination with chemotherapy."

 
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