Osteosarcoma and interferon. Studies of human xenografts in the nude mouse.
This work assessed the transplantability of human osteosarcomas to immunodeficient nude mice. Osteosarcomas serially transplanted in nude mice were characterized by growth rate, histologic features, and nuclear DNA content. The osteosarcoma xenografts were used to investigate the antitumor effects of interferon (IFN). Tumor tissue from 25 primary osteosarcomas was transplanted into nude mice. All tumors were histologically of high grade (III-IV). Flow DNA cytometry disclosed that all, except 1, had a nondiploid DNA content. 14 of the 25 osteosarcomas grew in serial passage in nude mice, i.e., the take rate was 0.6. The transplantable osteosarcoma group was characterized by a predominance of Grade IV lesions, and a high proportion of proliferating cells, compared to the nontransplantable. The 14 osteosarcoma xenografts, established in nude mice, were heterogeneous with respect to growth rate, histologic subtype, DNA content, and proliferative activity. However, the osteosarcomas retained the basic characteristics of their respective original tumor; the xenografts exhibited the same histologic appearance and DNA content in the first 2 passages in nude mice. During serial transplantation of the 14 osteosarcomas, the histologic features remained unaltered from passage to passage during the observation period of up to 3 years. The aneuploid DNA content was also unchanged over time in most tumors. However, in 4 osteosarcomas with 2 aneuploid cell populations, the cell population with the higher DNA content became predominant, while the other gradually disappeared. Hence, the changes in DNA content involved polyploidization, followed by selection of the cell population with higher DNA content. At the same time growth rate increased, but histologic features were unchanged. This study of osteosarcoma, serially transplanted in nude mice, shows that growth rate, histologic appearance, and DNA content are relatively stable tumor features. The observed changes in DNA content illustrate the development of aneuploidy in malignant tumors. The antitumor effects of human nIFN-alpha were assessed in the 14 osteosarcoma xenografts. In dose-response experiments, based on 2 different tumors, 2 x 10(5) IU/day of nIFN-alpha was found to arrest tumor growth. This dose was chosen as the standard dose in subsequent experiments. Among the 14 osteosarcomas, tumor regression or growth arrest was seen in 5, whereas 8 were only partially growth inhibited with the standard dose. The remaining osteosarcoma was growth inhibited with higher nIFN-alpha doses. Hence, all 14 analyzed osteosarcomas were sensitive to the antitumor effect of nIFN-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
Brosjö
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Department of Orthopedics, Karolinska Hospital, Stockholm, Sweden.
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000628:therapy*; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000473:pathology / Q000628:therapy*
D004273:DNA, Neoplasm; D007370:Interferon Type I; D007371:Interferon-gamma