Growth of astrocytomas in the human tumor clonogenic assay and sensitivity to mismatched dsRNA and interferons.

Nine astrocytoma specimens were received from seven patients and processed for testing in the human tumor clonogenic assay (HTCA). Cells derived from these specimens were challenged with human natural alpha-interferon (alpha-IFN) and beta interferon (beta-IFN), recombinant beta interferon (beta ser-IFN), and mismatched double-stranded (ds) RNA (Ampligen). Six of the astrocytoma specimens formed adequate colonies for drug sensitivity testing (greater than or equal to 30 colonies/plate), and all were high-grade (III-IV) tumors. Sensitivity was defined as a greater than or equal to 50% decrease in tumor colony formation following drug exposure and was observed with alpha-IFN (2/4), beta-IFN (3/4), and mismatched dsRNA (4/5) exposure. No decrease in colony growth was observed after recombinant beta ser-IFN exposure, and in 2 of 3 cases, colony formation was stimulated. The sensitivity of 75 non-CNS solid tumors to mismatched dsRNA was compared to the high-grade astrocytomas in the HTCA. Of the 10 additional histologic tumor types studied, carcinoid and renal cell carcinomas exhibited the greatest sensitivity to mismatched dsRNA: 63% and 52%, respectively. However, in comparison, 80% of the high-grade astrocytomas were sensitive, demonstrating that these gliomas are among the most sensitive of human tumors to mismatched dsRNA in vitro. Clinical trials of interferons and mismatched dsRNA, coupled with in vitro sensitivity studies, should further define their therapeutic potential.

Human neuroblastomas and abnormalities of chromosomes 1 and 17.

Structural rearrangements of chromosome 1p have been reported previously as a frequent finding in human neuroblastomas. In a review of karyotypes from 35 neuroblastomas (including 29 published cases and 6 unpublished tumors and cell lines), it was found that, in addition to the abnormalities of chromosome 1p (found in approximately 70% of cases), abnormalities involving only 2 other chromosome segments occurred with significant frequency (in 20% or more of cases) in this cancer. These abnormalities involved trisomies for the long arms of chromosomes 1 and 17. In addition, two novel cytogenetic aberrations, homogeneously staining regions and double minutes, were identified in two-thirds of the cases. It is postulated that the gene change(s) produced by the abnormalities of chromosome 1p in neuroblastoma play a primary role in the development of this cancer. The gene changes produced by the abnormalities of chromosomes 1q and 17q and by the homogeneously staining regions and double minutes are presumed to contribute to tumor progression.

Antiproliferative effect of natural beta interferon on fresh tumor cells analyzed in a clonogenic assay.

Natural beta interferon (beta IFN), derived from diploid fibroblasts, has been evaluated for its antiproliferative activity using a panel of twelve different histologic types of fresh human tumor cells. Thirty-nine percent (9/23) of the tumors showed a 70% or greater decrease in colony formation following exposure to 500 international reference units per ml of natural beta IFN, a concentration which is in the clinically achievable range. Interesting, is that leiomyosarcoma, a tumor relatively resistant to conventional chemotherapy, was uniformly sensitive (3/3) to natural beta IFN. Indeed, the antiproliferative activity of beta IFN was consistently superior (in 19/20 comparative assays) to the other conventional chemotherapeutic drugs evaluated for leiomyosarcomas. This study, which suggests that natural beta IFN exhibits significant antiproliferative activity on a variety of fresh human tumor cells, may be useful in orienting clinical trials with natural beta IFN (still in limited supply because of its unique physicochemical nature) to the more susceptible human malignancies.