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Gene therapy in ovarian cancer

In 1998, an estimated 25,400 new cases of ovarian cancer were diagnosed in the United States, and approximately 14,500 of those women are expected to die from the disease.¹ Current standard treatment for ovarian cancer includes surgery to remove all or most of the tumor followed by combination chemotherapy. Taxol with carboplatin or cisplatin is a commonly used front-line regimen. In patients who receive first-line chemotherapy with carboplatin and Taxol, the response rate is 70 percent, and the five-year survival rate is 55 percent.^2,3

In an effort to improve these poor overall survival statistics, a number of new and innovative treatment strategies have been developed. These methods include immunotherapy, sequential chemotherapy, new cytotoxic drugs and, most recently, gene therapy.

Gene therapy
Gene therapy involves the identification of a genetic mutation that is present in the patient's cancer cells. Once this mutation is identified, the patient is given the wild-type (normal) gene that corresponds to the mutated gene in the cancer cell. The cancer cells then can absorb the normal gene and, it is hoped, lose their malignant behavior.

In ovarian cancer patients, the p53 gene has been of particular interest. The normal p53 gene is present in all normal human cells and is involved in the process of growth and differentiation. Because cells lacking this normal gene grow in a malignant fashion, the gene has been labeled a tumor suppressor gene.

Between 50 percent and 80 percent of ovarian cancer patients have tumors demonstrating p53 mutations. Preclinical studies indicate that reintroduction of the wild-type p53 gene to cancer cells having a mutated p53 gene inhibits cell proliferation and results in cell death via apoptosis of this cell.⁴ Because of the high frequency of p53 mutations in ovarian cancer cells and the ability to reverse malignant behavior in cell culture with the addition of wild-type p53, a number of investigators are studying the use of the p53 gene in ovarian cancer patients.

Gene therapy with p53
Schering-Plough is a pharmaceutical company that is leading the way in the development of gene therapy. Schering-Plough has discovered a way to deliver the wild-type p53 gene to the cancer cells of ovarian cancer patients. This new product is labeled SCH58500. SCH58500 is a novel antineoplastic agent consisting of a recombinant adenovirus containing the cloned human wild-type p53 tumor suppressor gene. Several versions of recombinant adenovirus vectors containing p53, collectively designated rAd/p53, have been constructed. In each of these, the adenoviral vector is derived from adenovirus type 5, a common serotype belonging to subgroup C.

For SCH58500, the vector has been rendered replication-defective through the deletion of region E1, which contains the viral genes E1a, E1b and protein IX. The vector is propagated in the human embryonal kidney cell line 293, which contains adenoviral sequences to support replication of the otherwise replication defective SCH58500. A cDNA sequence encoding the entire open reading frame of human wild-type p53 gene has been inserted into the vector. Expression of p53 is directed by the highly efficient human cytomegalovirus immediate early promoter/enhancer element, while translation of p53 mRNA is enhanced by the addition of the adenovirus type-2 tripartite leader sequence. Completed phase I studies demonstrate an acceptable safety profile for SCH58500 alone and in combination with Taxol and carboplatin.

Clinical trial
A phase II/III trial of SCH58500 recently was launched in more than 50 sites in North America and Europe. Women with newly diagnosed stage III ovarian cancer or primary peritoneal cancer in which a p53 mutation has been detected are eligible to be considered for treatment with SCH58500. Patients must have a residual tumor greater than or equal to 0.5 cm and less than or equal to 2 cm following initial cytoductive surgery.

Ellis Fischel Cancer Center in Columbia, Mo., is one of the few institutions in the Midwest testing this agent. If you know of a woman who may be eligible for this new and promising therapy, please call our clinical trials office at (573) 882-7440 or the division of gynecologic oncology at (573) 882-1057.

References

1. Cancer facts and figures 1998: American Cancer Society:13-14.

2. Ten Bokkel Huinink W, Veenhohh C, Huizing M et al: Carboplatin and paclitaxel in patients with advanced ovarian cancer: a dose-finding study. Seminars in Oncology. 1997;24(2):31-33.

3. Ozols R: Gynecologic oncology group trials in ovarian carcinoma seminars in oncology. 1997;24(2):10-12.

4. Wills KN, Maneval DC, Menzel P et al: Development and characterization of recombinant adenoviruses encoding p53 for gene therapy of cancer. Human Gene Therapy. 1994;5:1079-1088.