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Conrad Notes
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ANTISENSE THERAPY (AT) BLOCKS CANCER GROWTH
B.I. Sikic, MD, Stanford University Medical Center, Stanford, Calif, described preliminary safety and efficacy results using antisense oligonucleotides, a short segment of modified deoxyribonucleic acid (DNA). Twenty-one day courses of continuous intravenous infusion of AT sought the gene responsible for making protein kinase C alpha. The 17 treated patients included various cancers: ovary, 4, colon, 3, pancreas, 3, nonspecific sarcoma, 3, and one each stomach, breast, lymphoma, lung and esophagus. This treatment appears to be well tolerated and showed shrinkage of tumor in one ovarian cancer patient.

Rationale for ATThe first step in protein synthesis involves transcribing the 4 bases (adenine, thymine, guanine and cytosine) onto one strand of DNA's double helix into the complementary sequence in a messenger RNA (mRNA) molecule. Proteins arise from these "sense" molecules.

A short stretch of oligonucleotides called antisense can be made to pair up with mRNA made from the PKC alpha gene. This gene is responsible for production of PKC alpha kinase needed for the continued growth of normal and cancer cells. The process called translocation normally converts the mRNA into protein. When bound to antisense DNA, this mRNA breaks down to block translation and results in turning off protein production. Fortunately, PKC alpha kinase in cancer cells is more sensitive to antisense treatment than in normal cells.

Procedure for treatment An ambulatory pump provided continuous intravenous infusion of ISIS 3521, a 20-base phosphothiolate oligonucleotide which is complementary to the 3'-untranslated region of mRNA for human PKC alpha. The test group of 17 patients started initially at 0.5 mg/kg/day x 21 days followed by a week off ISIS 3521. Each group of three patients alternated in dose-ranging at 1.0, 1.5, 2.0, and 3.0 mg/kg/day following the same cycling schedule.
Safety of ISI 3521 The 3 mg/kg/day schedule produced mild to severe toxicity such as grade 2 decrease in platelets, 4/17, grade 3 fatigue, 2/17, grade 4 thrombocytopenia, 1/17, and mild leukopenia, 2/17. These findings led Sikic to rate the treatment as well-tolerated.
Effectiveness of ISI 3521 CT scans showed a 50% decrease in the ovarian cancer of one patient (partial response) at about 10 months of treatment. The starting dose in this patient was 0.5 mg/kg and since safe, finally escalated to 2 mg/kg/day. Two additional ovarian cancer patients had early signs (decreased CA-125 levels) of an antitumor effect at one and two months' treatment. One colon cancer patient experienced tumor stabilization for 4 months before tumor progression.
Comments The very preliminary data on ISIS 3521 follow initial transfer of a cancer treatment concept from the laboratory to patients. Sikic and associates plan to conduct further studies in ovarian and lung cancer patients using AT alone and in combination with standard chemotherapies.

Eugene A. Conrad

Presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) on May 17-20, 1997
CONRAD NOTES, © 1997 All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078 / June 1997

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