Perspectives On Animal Research

Volume 1, Supplement

An Evaluation of Ten Randomly-Chosen Animal Models of Human Disease

Osteosarcoma (Rats)

(1)

Description of the Model:

Olson and Capen described the induction of osteosarcoma in rats by intratibial inoculation with Moloney sarcoma virus (MSV).(1) This model, they maintained, is superior to other animal models of osteosarcoma. Other models, in which agents are injected via intravenous or intraperitoneal routes, tend to produce multiple sarcomas involving several tissues. Olson and Capen wrote, "The MSV-induced osteosarcoma in the rat should be a valuable animal model to investigate the biological behavior of osteosarcoma and to evaluate new therapeutic regimens." (1)

Criterion I: Concordance between the Animal Model and the Human Disease

Clinical Presentation:

Rat and human osteosarcoma have some gross similarities in clinical presentation, but there are several difficulties with the animal model. For example, rats inoculated later in life have markedly different presentations from rats inoculated shortly after birth. Olson and Capen observed:

Compared to rats inoculated on Day 1 after birth, rats inoculated at 4 days of age developed consistently more osteoproliferative bone tumors that often were associated with hypercalcemia, increased serum alkaline phosphatase, and elevated urinary hydroxyproline.(2)

Furthermore:

Osteosarcomas in rats inoculated on Day 4 of age were radiodense, firm and contained abundant mineralized stroma. Conversely, rats inoculated on Day 1 of age developed osteosarcomas with large radiolucent zones that were fleshy and contained extensive areas of necrosis.(3)

Finally:

Rats inoculated with SVP (standard viral preparation) at Day 15 or 20 after birth did not develop osteosareomas within 50 days pi (post injection). Evaluation of tumors from rats receiving SVP revealed considerable histologic variability depending on the age of the rat at the time of inoculation.(3)

In contrast, presentation of osteosarcoma in people does not appear to depend on age. Lockshin and Higgins noted, "Age probably does not directly influence prognosis."(4) He cited a 1957 study that found a 21.2 percent five-year survival for patients diagnosed before age 30, compared to 14.3 percent for patients diagnosed after age 30.(4) Rats with a later onset of osteosarcoma have more differentiated tumors that presumably carry a better prognosis, but human patients with later onset of disease may have a worse prognosis.

Another general problem is that both rat and human osteosarcoma are heterogenous conditions. Thus, there is no discrete animal model, but rather a broad range of clinical and histological presentations.(3,5) This makes it difficult to apply laboratory findings to human patients.

Pathogenesis:

The MSV-induced rat model appears to have a different etiology from human osteosarcoma. While viral particles have not been located in human osteosarcomas,(3) they are present in osteosarcomas induced by MSV. Olson and Capen noted, "...viral particles were present within the cytoplasm of tumor cells and were observed budding from the plasma membrane."(2) There is some indirect evidence that suggests a viral etiology in human osteosarcoma, (6,7) but the cause of the disease remains unknown.(8) In their recent review of osteosarcoma, Goorin et al. noted that ionizing radiation and genetic factors predispose to human osteosarcoma, but they did not mention a possible viral etiology.(8)

One must use caution when comparing the results of induced tumors in rodents with spontaneous osteosarcomas in people, particularly when it appears that the pathogenesis differs. One way to determine whether or not induced tumors are representative of osteosarcomas in general is to compare induced osteosarcomas in rats to spontaneously occurring osteosarcomas in rats. If they are similar, it will lend some credence to the notion that induced tumors in rats may be similar to spontaneous tumors in man. Ruben et al. reported a spontaneous osteosarcoma in the rat and reviewed the literature.9 Although they found metastases in their own case, most of the 27 cases reported in the literature were non-metastatic.9 Thus, spontaneous osteosarcoma in rats appears to differ markedly from both induced osteosarcoma in rats and from spontaneous osteosarcoma in people.

Criterion II: Citations

Eleven articles listed in the Science Citation Index from 1977 to 1988 cited at least one of the two main articles that described this animal model.(2,3) (See Appendix A.) All were animal research studies, with the exception of a review article by Wlodarski.(10) He wrote, "...murine Moloney sarcoma virus induces at the site of inoculation in newborn and adult mice and rats various types of sarcoma, including osteosarcoma."(10)

Criterion III: Historical Impact

Olson and Capen predicted that their model would be valuable in the testing of chemotherapeutics. The only article from the Science Citation Index review that actually used this model to test an anti-cancer drug was a study by Olson and Capen on Adriainycin treatment.(11) They reported, "...chronic administration of low doses of ADR (Adriamycin) can significantly reduce the mortality rate of osteosarcoma bearing NZB rats." (11) However, "Present data suggest that ADR-induced cardiotoxicity may be an important factor in causing the death of the osteosarcoma-bearing rat ..." (11) In contrast, while cardiotoxicity is an important concern in human patients, "Leukopenia is the usual dose-limiting toxicity..."(12) While it was already known that Adriamycin improves survival in human patients with osteosarcoma, the authors concluded:

The sensitivity of the osteosarcoma-bearing New Zealand black rat to the antitumor and cardiomyopathic effects of Adriamycin provides an animal system for evaluation of the oncolytic activity of new analogs as well as their cardiotoxic potential.(11)

Despite the hopeful predictions of relevance for their model, all six citations of this paper (11) from 1978 to 1987 were animal research studies.

Goorin et al. reviewed human osteosarcoma in 1985.(8) Of the 99 papers cited, only two involved animal research. Both documented experimental evidence that chemotherapy is more effective against microscopic tumor than macroscopic tumor. Neither study involved an animal model of osteosarcoma. There was no mention of research with the rat model of osteosarcoma.

Conclusions:

There appear to be fundamental differences in the pathogenesis of MSV-induced osteosarcomas in rodents and osteosarcomas in people. The broad range of clinical presentation further compromises attempts to apply research fmdings to human patients. Perhaps because of these problems, a recent clinical review did not cite any data derived from use of the MSV-induced rat model. Thus, it appears that this animal model of osteosarcoma has not been relevant to human osteosarcoma.

References:

1. Olson HM, Capen CC. Osteosarcoma, Model No. 114, in Jones TC, Hackel DB, Migaki G, (Eds), Handbook Animal Models of Human Disease Fasc. 6. Washington DC, Registry of Comparative Pathology, Armed Forces Institute of Pathology, 1977.

2. Olsen HM, Capen CC Intratibial Moloney sarcoma virus-induced osteosarcoma in the rat: Tumor incidence and pathologic evaluation. J Natl Canc Inst 1977;58:433-435.

3. Olson HM, Capen CC Viris-induced animal model of osteosarcoma in the rat. Am J Pathol 1977;86:437-458.

4. Lockshin MD, Higgins ITT. Prognosis in osteogenic sarcoma. Clin Orthop 1968;58:85-103.

5. Braunwald E, Isselbacher U, Petersdorf RG, Wilson JD, Martin JB, Fauci AS. Harrison's Principles of Internal Medicine, 11th Ed. New York, McGraw-Hill, 1987, pp 1905-1906.

6. Morton DL, Malmgren RA. Human osteosarcomas: Immunologic evidence suggesting an associated infectious agent Science 1968;162:1279-1281.

7. Pritchard DL, Reilly CA, Finkel MP. Evidence for a human osteosarcoma virus. Nature (New Biol) 1971;234:126-127.

8. Goorin AM, Abelson HT, Frei E. Osteosarcoma: Fifteen years later. New Engl J Med 1985;313:1637-1643.

9. Rubin Z, Rohrbacher E. Spontaneous osteogenic sarcoma in the rat. J Comp Pathol 1986;96:89-94.

10. Wlodarski KH. Orthotopic and ectopic chondrogenesis and osteogenesis mediated by neoplastic cells. Clin Orthop 1985;200:248-265.

11. Olson HM, Capen CC. Chemoresponsiveness of Moloney sarcoma virus-induced osteosarcoma to adriamycin in the rat. Canc Res 1978;38:1561-1567.

12. AMA Division of Drugs. AMA Drug Evaluation, Fifth Edition. Chicago, American Medical Association, 1983, pp 1534-1535.