Combination of radiotherapy and anti-angiogenic factors

Details Combination of radiotherapy and anti-angiogenic factors Combination of radiotherapy and anti-angiogenic factors

1999-06-16

2002-07-16

Priebe, Scott D. (Department: 1632)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S350000, C378S065000, C514S001000, C600S001000

Reexamination Certificate

active

06420335

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of neovascularization and cancer therapy. More particularly, it concerns the methods and compositions for treating cancer growth by first inhibiting angiogenesis and then employing radiotherapy.
2. Description of Related Art
Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and cell death. Disruption of this balance either by increasing the rate of cell proliferation or decreasing the rate of cell death can result in the abnormal growth of cells and is thought to be a major event in the development of cancer. The effects of cancer are catastrophic, causing over half a million deaths per year in the United States alone. Conventional strategies for the treatment of cancer include chemotherapy, radiotherapy, surgery, biological therapy or combinations thereof; however further advances in these strategies are limited by lack of specificity and excessive toxicity to normal tissues. In addition, certain cancers are refractory to treatments such as chemotherapy, and some of these strategies such as surgery are not always viable alternatives.
Once the diagnosis of cancer is established, the most urgent question is whether the disease is localized, or has spread to lymph nodes and distant organs. The most fearsome aspect of cancer is metastasis, and this fear is well justified. In nearly 50% of patients, surgical excision of primary neoplasms is ineffective, because metastasis has occurred by the time the tumor is large enough for resection (Sugarbaker, 1977; Fidler and Balch, 1987). Metastases can be located in different organs and in different regions of the same organ, making complete eradication by surgery, radiation, drugs, or biotherapy difficult. Furthermore, the organ microenvironment significantly influences the response of tumor cells to therapy (Fidler, 1995), as well as the efficiency of anticancer drugs, which must be delivered to tumor foci in amounts sufficient to destroy cells without leading to undesirable side effects (Fidler and Poste, 1985). In addition, the treatment of metastatic cancer is greatly hindered due to the biological heterogeneity of cancer cells, and the rapid emergence of tumor cells that become resistant to most conventional anticancer agents (Fidler and Poste, 1985).
One of the processes involved in the growth of both primary and secondary (metastatic) tumors is neovascularization, or creation of new blood vessels which grow into the tumor. This neovascularization is termed angiogenesis (Folkman, 1986, 1989), which provides the growing tumor with a blood supply and essential nutrients. Although tumors of 1-2 mm in diameter can receive all nutrients by diffusion, further growth depends on the development of an adequate blood supply through angiogenesis. Inhibition of angiogenesis provides a novel and more general approach for treating both primary and secondary tumors by manipulation of the host microenvironment.
The induction of angiogenesis is mediated by several angiogenic molecules released by tumor cells, tumor associated endothelial cells and the normal cells surrounding the tumor endothelial cells. The prevascular stage of a tumor is associated with local benign tumors, whereas the vascular stage is associated with tumors capable of metastasizing. Moreover, studies using light microscopy and immunohistochemistry concluded that the number and density of microvessels in different human cancers directly correlate with their potential to invade and produce metastasis (Weidner et al., 1991, 1993). Not all angiogenic tumors produce metastasis, but the inhibition of angiogenesis prevents the growth of tumor endothelial cells at both the primary and secondary sites and thus can prevent the emergence of metastases.
Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
Persistent and unregulated angiogenesis is characteristic of tumor growth and it supports the pathological damage seen in these cancer. Thus, tumor growth is an angiogenesis-dependent process (Folkman, 1971). After an initial prevascular phase, every increase in tumor endothelial cell population is preceded by an increase in new capillaries converging on the tumor. Expansion of tumor volume beyond this phase requires the induction of new capillary blood vessels.
It has been demonstrated that in mice bearing Lewis lung carcinoma (3LL) subcutaneously (s.c.), the primary or local tumor releases an angiogenesis-inhibiting substance, named angiostatin (O'Reilly et al. 1994). Angiostatin is a 38-kDa fragment of plasminogen that selectively inhibits proliferation of endothelial cells. Angiostatin has been shown to suppresses vascularization and, hence, growth of metastases when used as an adjuvant to conventional therapy (U.S. Pat. No. 5,733,876, specifically incorporated herein by reference). Several studies have produced results consistent with this model. After systemic administration, purified angiostatin can produce apoptosis in metastases (Holmgren et al., 1995) and sustain dormancy of several human tumors implanted subcutaneously in nude mice (O'Reilly et al., 1996). However, although it is known that angiostatin can be generated in vitro from plasminogen by digestion with pancreatic elastase (O'Reilly, 1994), how it is generated in vivo in tumors remains unclear. Recently a second peptide, endostatin, was identified as a potential inhibitor of angiogenesis (O'Reilly et al., 1997). Endostatin, produced by hemangioendothelioma, is a 20 kDa C-terminal proteolytic fragment of collagen XVIII (Hohenester et al., 1998). Endostatin specifically inhibits endothelial proliferation and is postulated to inhibit angiogenesis and tumor growth.
Clearly, angiogenesis plays a major role in cancer development and maintenance. As stated earlier, conventional cancer therapeutic regimens are hampered by the ability of the cancer cell to adapt and become resistant to the therapeutic modality used to combat tumor growth. Although, it has been suggested that angiostatin may be useful in reducing the growth, size and otherwise mitigating the deleterious effect of a tumor, there is presently no objective evidence to suggest that angiostatin or endostatin could be used to weaken a tumor such that it would subsequently be amenable to radiotherapy.
SUMMARY OF THE INVENTION
Thus, the present invention provides a method of sensitizing a cell to ionizing radiation comprising the steps of first contacting the cell with an anti-angiogenic factor in an amount effective to sensitize the cell to ionizing radiation; and then exposing the cell to a dose of ionizing radiation effective to inhibit the growth of the cell.
In particularly preferred embodiments, the cell is an endothelial cell lining blood vessels that supply a tumor, defined hereafter as a tumor endothelial cell. In more defined embodiments, the tumor endothelial cell is located within an animal, and the contacting comprises in vivo delivery of the anti-angiogenic factor. In certain embodiments, the contacting is effected by direct injection of the tumor with the anti-angiogenic factor. In other embodiments, the contacting is effected by regional delivery of the anti-angiogenic factor. In still another embodiment, the contacting is effected by local delivery of the anti-angiogenic factor. In preferred embodiment

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