Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
2000-04-10
2002-03-26
Clark, Deborah J. R. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C424S009100, C424S009200, C424S093100, C800S008000, C800S009000
Reexamination Certificate
active
06362392
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to animal models for the growth and treatment of human neurally-derived tumors and the treatment of neurofibrosarcoma tumors using a therapeutic regimen which inhibits angiogenesis and tumor vascularization.
2. Description of the Background Art
Neurofibromatosis is an autosomal dominant genetic disorder associated with the development of multiple benign tumors and occasional malignant tumors. No effective treatment is available for either form of tumor and the malignant tumors, neurofibrosarcomas, are usually fatal despite aggressive surgical, medical, and radiotherapeutic treatment regimens (Martuza, R. L.,
Neurosurgery
, MacGraw-Hill, Vol. 1, 1984, pp. 511-521). Therefore, new approaches for the treatment of neurofibrosarcomas would be of enormous benefit at this time.
It has become increasingly evident that angiogenesis, the formation of blood vasculature, is a fundamental and necessary event in the growth of solid tumors (Brem, S.,
CNS
23:440-453 (1976); Folkman, J. et al.,
J. Exp. Med
. 133:275-288 (1971); Folkman, J.,
Ann. Surg
. 175:409-416 (1972); Folkman, J.,
Adv. Cancer Res
. 43:175-203 (1985); Folkman, J. et al.,
Science
235:442-447 (1987); Greenblatt, M. et al.,
J. Nat. Cancer Inst
. 41:111-124 (1968); Klagsbrun, M. et al.,
Cancer Res
. 36:110-114 (1976); Rastinejad, F. et al.,
Cell
56:345-355 (1989); Tannock, J. F., Br.
J. Cancer
22:258-273 (1968); Tannock, J. F.,
Canc. Res
. 30:2470-2476 (1970); Thompson, J. A. et al.,
Science
241:1349-1352 (1988). Zagzag, D. et al.,
Am. J. Pathol
. 131:361-372 (1988); Ziche, M. et al.,
JNCI
69:483-487 (1982)). Thus, therapeutic strategies directed at disrupting this process are expected to be important. Following establishment of a blood supply, tumor cells not only begin to grow but also acquire the potential for metastasizing to distant sites by entering the circulation through this new vasculature (Folkman, J.,
Adv. Cancer Res
., supra). Invasiveness of neoplastic cells in several in vitro, in vivo, and in situ models has indeed been linked to angiogenesis (Brem, S., Proc.
Amer. Assoc. Neurol. Surgeons Ann. Meet
. Washington, D.C., 1989, p.382 (abst)).
Tumor angiocyenesis is induced by soluble tumor angiogenesis factors produced by tumor cells (Folkman, J. et al., 1971, supra; Folkman, J., 1985, supra). Several angiogenic factors, such as the fibroblast growth factors (&agr;FGF and &bgr;FGF), angiogenin, and the transforming growth factors, TGF-&agr; and TGF-&bgr;, have been purified, their amino acid sequences detennined, and their genes cloned (Folkman, J. et al., 1987, supra). These studies led to a hypothesis that solid tumors are angiogenesis-dependent, and that “anti-angiogenesis” was a potential approach to tumor therapy.
The art of angiogenesis research has relied mainly on three models for the ini vivo study of capillary proliferation: (1) The rabbit and rodent cornea micropocket; (2) the chicken embryo chorloallantoic membrane; and (3) the hamster cheek pouch for murine experimental tumors (Folkman, J., 1985, supra; Folkman, J. et al., 1987, supra; Greenblatt, M. et al., supra; and Zagzag, D. et al., supra).
In 1983, Folkman's group disclosed that heparin or a heparin fragment administered with cortisone, caused regression of large tumor masses and prevented metastases (Folkman, J. et al.,
Science
221:719-725 (1983)). Angiogenesis was inhibited when heparin, or one of its fragments lacking anti-coagyulant activity, was administered simultaneously with an angiostatic steroid. This was somewhat paradoxical given the fact that heparin alone actually promotes angiogenesis in vivo and can potentiate endothelial locomotion and proliferation in vitro. The angiostatic steroids by themselves had weak or no angiogenesis-inhibiting activity (Crum, R. et al.,
Science
230:1375-1378 (1985)). Potent inhibition of angiogenesis required the “pair” effect of two components.
Despite the promise of this approach, the literature reflects disparate results; some investigators have observed inhibition oftumor growth with heparin plus cortisone whereas others have not (Lee, K. et al.,
Canc. Res
. 47:5201-5204 (1987); Penhaglion, M. et al., .
JNCI
74:869-873 (1985); Rorg, G. H. et al.,
Cancer
57:586-590 (1986); Sakamoto, N. et al.,
JNCI
78:581-585 (1987); and Ziche, M. et al.,
Int. J. Cancer
35:549-552 (1985)).
For tumors that were responsive to heparin and cortisone, oral administration of 200 units of heparin per ml of drinking water was generally found to be the minimum effective dose, and tumor regression was more rapid as the dose increased up to 1000 units/ml. However, when the heparin dose was increased further, for example, to 2000-5000 units/ml, rapid tumor growth rather than regression was observed (Crum, R. et al., 1985, supra).
The efficacy of heparin was found to depend critically on the source of the heparin. The most potent, Panheparin
R
(Abbott Laboratories), is no longer commercially available. The next most potent heparin, from Hepar, Inc., Franklin, Ohio) was noted to cause regression of reticulum cell sarcoma, but not of Lewis lung carcinoma, in mice (Folkman, J. et al., 1983, supra). Heparin preparations are frequently heterogeneous in composition, molecular size, sequence, and position of substituents (N-sulfate, O-sulfate, and glucuronic acid). This may account for the differences in anti-tumor efficacy when the heparin is used in combination with angiostatic steroids (Folkman, J. et al.,
Science
243:1490-1493 (1989)). However, these reports tested only malignant murine tumors which may be particularly resistant to such therapy. The ability to test anti-angiogenic agents, alone or in combination, on human tumors would be of great benefit for devising therapeutic strategies.
Animal models are important tools for studying the growth and spread of human tumors and for developing and testing therapeutic strategies. The development of congenitally athymic “nude” mice and refinement of techniques for producing immunodeficiencies in rodents have permitted more detailed study of a variety of xenotransplanted human tumors (Aamdal, S. et al.,
Int. J. Cancer
34:725-730 (1984); Abernathey, C. D. et al.,
Neurosiirgery
22:877-881 (1988); Bailey, M. J. et al.,
Br. J. Cancer
50:721-724 (1984); Bigner, S. H. et al., .
J. Neuropathol. Exp. Neurol
. 40:390-409 (1981); Dumont, P. et al.,
Int. J. Cancer
33:447-451 (1984); Epstein, A. L. et al.,
Cancer
37:2158-2176 (1976); Giovanella, B. et al.,
Adv. Cancer Res
. 44:69-129 (1985); Rajnay, J. et al.,
Oncology
44:307-311 (1987); Rao, M. S. et al., .
J Pathology
135:169-177 (1981); Schold, S. C. et al.,
Prog. Exp. Tumor Res
. 28:18-31 (1984)).
Several human brain tumor models involving subcutaneous (s.c.) or intracerebral (i.c.) implants in nude mice, have been reported (Basler, G. A. et al., in
The Nude Mouse in Experimental and Clinical Research
, Fogh, J. et al. (eds.), New York: Academic Press, Vol. 2, pp. 475-490 (1982); Bradley, N. J. et al.,
Br. J. Cancer
38:263-272 (1978); Bullard, D. E. et al.,
Neurosurgery
4:308-314 (1979); Horten, B. C. et al.,
J. Neuropathol. Exp. Neurol
. 40:493-511 (1981); O'Sullivan, J. P. et al.,
J. Endocr
. 79:139-140 (1978); Rana, M. W. et al.,
Proc. Soc. Exp. Biol. Med
. 155:85-88(1977); Shapiro, W. R. et al.,
J. Natl. Cancer Inst
. 62:447-453 (1979); Slagel, D. E. et al.,
Cancer Res
. 42:812-816 (1982); Tueni, E. A. et al.,
Eur. J. Cancer Clin. Oncol
. 28:1163-1167 (1987); Ueyama, Y et al.,
Br. J. Cancer
37:644-647 (1978)).
In vivo models oftumors grown in nude mice have been extremely useful for a wide variety of purposes, such as studying tumor biology and testing, sensitivity to chemotherapy and radiotherapy. Although s.c. xenografts allow serial tumor volume measurements, and the procedureof implantation is easy, the s.c. tumors are difficult to measure precisely with calipers since they may be surrounded by fibrous tissue or fat. Many neural tumors typically grow slowly. A short-term method for the g
Lee Jung Kyo
Martuza Robert L.
Baker Anne-Marie
Clark Deborah J. R.
Sterne Kessler Goldstein & Fox PLLC
The General Hospital Corporation
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