Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Coated – impregnated – or colloidal particulate
Reexamination Certificate
1999-07-29
2003-11-11
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Coated, impregnated, or colloidal particulate
C424S001290, C424S001170, C424S001110, C424S001650, C424S009300, C424S009320, C424S009321, C424S009323, C435S173600, C435S173400, C435S173500, C435S285200, C435S002000
Reexamination Certificate
active
06645464
ABSTRACT:
BACKGROUND
1. Field of Invention
This invention relates to medical imaging and therapy.
2. Discussion of Prior Art
Cancer Therapy
The National Cancer Institute estimates that over 1,200,000 new cases of invasive cancer will be diagnosed this year in the United States. This means that 46.6% of men (1 in 2) and 38.0% of women (1 in 3) will develop invasive cancer during their lifetime.
Although advances in treatment have occurred, unfortunately each year, more than 550,000 Americans die of cancer—more than 1,500 people a day. It is the second leading cause of death after heart disease. The financial costs of cancer are also staggering. The National Cancer Institute estimates overall annual costs for cancer at $107 billion.
Existing Therapies
Treatment of cancer is an area of intense research interest, and an urgent priority for world health. Although much progress has been made, much effort must still be expended to achieve fully satisfactory tumor control using effective and economical methods. Surgery, radiation, and chemotherapy remain the principal modalities of treatment. New chemotherapeutic agents such as paclitaxel (Johnson D H, J. Natl. Cancer Inst. Monogr. 19, 61, 1995) have been proven highly effective against some cancers, including breast, advanced ovarian, Kaposi's and non-small-cell lung cancers. Our rapidly expanding knowledge of tumor biology has enabled the development of important new approaches to therapy. Elucidation of the structure and function of the receptors and proteins expressed during tumor growth have enabled the development of a new generation of highly effective antibodies for immunotherapy; for example, humanized monoclonal antibodies against the Her-2
eu protein p185 overexpressed in more aggressive breast tumors have proven to be effective against advanced breast cancer (Baselga, J. et al. J. Clin. Oncol. 14, 737, 1996). Understanding the genetics of cancer, and the role of oncogenes and gene amplification has enabled researchers to pursue therapies which directly target the genetic abnormalities found in tumor cells, such as antisense therapy (Hung, M. C. et al. Gene,159, 65, 1995) and gene therapy (Yan, D. H. Biochem. Biophys. Res. Commun. 246, 353, 1998). Research into the molecular basis for the effect of tumors on surrounding blood vessels (angiogenesis, Fidler, I. J., et al. Cancer J. Sci. Am., Suppl. 1, 4, S58, 1998) has brought a new class of therapeutics into consideration which intervene in this process, such as anti-angiogenic antibodies (Presta, L. G., et al. Cancer Res. 57, 4593, 1997), peptides and polypeptides such as angiostatin, endostatin, and VEGF (Boehm, T., et al. Nature 390, 404, 1997). However, these approaches alone have not resulted in universal new therapies: for effective application, they require intensive research into those processes in the specific cancer to which the therapy is targeted.
Significant advances have also been made in liposome delivery agents (Dass, C. R. agents such as boron compounds for Boron Neutron Capture Therapy (BNCT, Gahbauer, R. et al. Recent Results Cancer Res. 150, 183, 1998) and radioimmunochelates for radiotherapy (Faivre-Chauvet, A. et al., Nucl. Med. Comm. 17, 781, 1996) has made these approaches more clinically relevant.
The most commonly used therapies are surgery, radiation, and chemotherapy. The deficiencies of each treatment are well known: Surgery cannot be used with inoperable tumors, for example in the brain or when vital organs are entangled, or fails to prevent recurrences when not all of the tumor and metastases are removed. Radiation frequently has a limited benefit: lethal doses to normal tissue must be avoided, therefore making the required tumoricidal dose unachievable; also some tumors are radioresistant: “ . . . hypoxia in solid tumors leads to resistance to radiotherapy and to some anticancer drugs” (Brown, J. M. and Giaccia, A. J., Cancer Research, 58, 1408-16, 1998). Chemotherapy suffers from toxicity, limiting the amount of drug that can be administered. “The use of chemotherapeutic agents in the therapy of cancer has led many physicians to increase the dose of these agent in the hopes of increasing efficacy. Increasing dosages caused an increase in the toxicity, which was occasionally life threatening and required aggressive therapeutic measures.” (Mittleman, A. “Life-threatening toxicity of cancer therapy”, Crit. Care Clin. 4, 1-9, 1998); “ . . . chemotherapy and whole brain radiation are associated with acute, subacute, and delayed toxicities”, (Moore, I. M., “Central nervous system toxicity of cancer therapy in children”, J. Pdiatr. Oncol. Nurs. 12, 203-210, 1995).
Newer, experimental therapies and drugs may seem promising, but these too, have shown shortcomings. They are useful, however, since they have provided relief or remission in some cases. Anti-angiogenic therapy, which attempts to prevent proliferation of blood vessels required to support tumor growth, is an interesting new method, but clinical trials have often been disappointing, and most patients continue to succumb. Radioimmunotherapy has been tried, but the toxicity of radiation delivered to non-tumor tissue has limited its use and success. Gene therapy has likewise thus far not been generally successful clinically; “ . . . current strategies for oligonucleotide-directed triple helix formation suffer from important constraints involving requirements for stabilizing binding conditions, restrictions on permitted target sequences, and inefficient nuclear delivery of oligonucleotides. Implementation of oligonucleotide-directed triple helix formation as a viable approach to cancer therapy must therefore await clever solutions to a series of fascinating problems.” (Maher, L. J. 3
rd
,“Prospects for the therapeutic use of antigene oligonucleotides”, Cancer Invest. 14, 66-82, 1996). Antibody therapy has shown to be of some benefit for certain cancers, but many do not respond. Boron neutron capture therapy has been under development for over 20 years and even now does not improve patient survival over conventional therapy. New drugs, such as paclitaxel and others have shown promise, extending life in some individuals, but recurrences and non-responders are common.
Although progress is being made, the cancer death rate has sadly not improved significantly over the years. It is fair to say that with so much effort and expense in cancer research, the development of a substantial new therapy that overcomes the limitations of previous attempts and current technology is not obvious.
Surgery attempts to remove the tumor, which is not completely possible in many cases. Cells that have metastasized and spread are not removed. Also, some tumor cells may be physically left behind and then regrow the tumor. Other tumor cells may be too difficult for the surgeon to selectively remove without risking important other tissues, commonly the case in pancreatic, brain, and liver cancer. An additional type of therapy used in conjunction with surgery is therefore required. Most other cancer therapies are based upon a cytotoxic effect, for example, the use of radiation and drugs. The toxic agent or radiation must be directed to the tumor since these are also toxic to normal tissues. Herein lies the problem. Useful chemotherapeutic drugs have some enhanced targeting or effect on tumor cells, but unfortunately they are still toxic to normal cells as the dose is raised, frequently limiting delivery of enough to eradicate all of the tumor. Similarly, radiation treatments, although regionally directed, still hit normal tissue, limiting the dose. Because some tumors or tumor regions are resistant to radiotherapy, this also limits effectiveness. What is needed in an improved therapy is more selective delivery of the cytotoxic effect to tumor cells.
Complete eradication of the tumor is a formidable task. Solid tumors (carcinomas) have been shown to be microscopically heterogeneous e.g., in expression of tumor markers and growth. Most anticancer drugs or therapeutic agents (including chemicals, nucleic acids, antibodies, radiois
Atwood Pierce
Farrell Kevin M.
Sharareh Shahnam J
Travers Russell
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