Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant...
Reexamination Certificate
2001-08-30
2004-01-27
Riley, Jezia (Department: 1637)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
C514S001000, C514S04400A, C536S025300
Reexamination Certificate
active
06682715
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field Of The Invention
The present invention relates to methods, compounds, and compositions for diagnosing and/or treating tumor cells with anti-tumor agents activated by thymidylate synthase (TS) and/or thymidine kinase (TK). In addition, the present invention relates to the preparation and use of positron emitting nucleoside analogues for use in imaging applications. The nucleoside analogues used in imaging applications may be of the type activated by TS or, in other embodiments, may not require activation by TS. More particularly, the present invention relates to methods for diagnosing and/or treating tumor cells by administration of compounds such as nucleoside analogue prodrugs and related compounds or compositions containing these in an effective amount to identify susceptible tumors in biopsy specimens or via external imaging, and then proceeding to reduce or inhibit the replication or spread of tumor cells.
2. Technology Review
Thymidylate synthase (TS) is an essential enzyme for DNA synthesis. It is, however, more abundant in tumor cells than in normal tissues. For decades, research and clinical studies have been directed towards inhibition of TS in order to shrink tumors. In some instances, this strategy has been modestly successful, for example, fluorouracil and floxuridine are utilized in the treatment of breast, colon, pancreas, stomach, ovarian, and head
eck carcinomas as disclosed by Chu E, Takimoto C H. “Antimetabolites.” In: DeVita V T Jr., Hellman S, Rosenberg S A, editors,
Cancer: Principles and Practice of Oncoloy,
Vol 1. 4th ed. Philadelphia: Lippincott, 1993:358-374.
Unfortunately, most tumors are inherently resistant to this strategy, and even those tumors, which are initially sensitive, develop resistance during the course of treatment as reported by Swain S M, Lippman M E, Egan E F, Drake J C, Steinberg S M, Allegra C J, in “Fluorouracil and High-Dose Leucovorin in Previously Treated Patients with Metastatic Breast Cancer,”
J. Clin. Oncol,
1989; 7:890-9. Recent applications of molecular probes for TS have demonstrated a consistent relationship between resistance and high expression of TS as noted in the following articles: Johnston P G, Mick R, Recant W, Behan K A, Dolan M E, Ratain M J, et al. “Thymidylate Synthase Expression and Response to Neoadjuvant Chemotherapy in Patients with Advanced Head and Neck Cancer”,
J. Natl. Cancer Inst.
1997; 89:308-13; Lenz H J, Leichman C G, Danenberg K D, Danenberg P V, Groshen S, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Garcia Y, Li J, Leichman L, “Thymidylate Synthase mRNA Level in Adenocarcinoma of the Stomach: A Predictor for Primary Tumor Response and Overall Survival”,
J. Clin. Oncol.
1996; 14:176-82; Johnston P G, Lenz H J, Leichman C G, Danenberg K D, Allegra C J, Danenberg P V, Leichman L, “Thymidylate Synthase Gene and Protein Expression Correlate and Are Associated with Response to 5-Fluorouracil in Human Colorectal and Gastric Tumors”,
Cancer Res
1995; 55:1407-12; Leichman L, Lenz H J, Leichman C G, Groshen S. Danenberg K, Baranda J, et al, “Quantitation of Intratumoral Thymidylate Synthase Expression Predicts for Resistance to Protracted Infusion of 5-Fluorouracil and Weekly Leucovorin in Disseminated Colorectal Cancers: Preliminary Report from an Ongoing Trial”,
Eur. J. Cancer
1995; 31:A 1305-10. Kornmann M, Link K H, Staib L., Danenberg P V., “Quantitation of Intratumoral Thymidylate Synthase Predicts Response and Resistance to Hepatic Artery Infusion with Fluoropyrimidines in Patients with Colorectal Metastases”,
Proc. AACR
38:614,1997.
A new generation of drugs designed to inhibit TS is reported by Touroutoglou N, Pazdur R. in “Thymidylate Synthase Inhibitors”,
Clin. Cancer Res.
1996; 2:227-43, to be currently in final stages of clinical testing. Despite the enormous resources which are being expended to improve the effectiveness of first-generation TS inhibitors, neither the existing drugs nor this new set of compounds are effective in tumors which have a high level of TS activity. Presently, once a tumor has become resistant due to-high levels of TS, there is no specific therapy available.
Instead of inhibiting TS, the present inventors hypothesized that is was possible to use this enzyme to activate uridine analogue prodrugs into more toxic thymidine analogues. The present inventors have previously demonstrated in
Molecular Pharmacology,
46: 1204-1209, (1994) in an article entitled, “Toxicity, Metabolism, DNA Incorporation with Lack of Repair, and Lactate Production for 1-2′Fluoro-2′deoxy-&bgr;-D-arabinofuranosyl)-5-iodouracil (FIAU) in U-937 and MOLT-4 Cells” that 1-(2′Fluoro-2′deoxy-&bgr;-D-arabinofuranosyl)-uracil (FAU) was phosphorylated intracellularly by intact U-937 and MOLT-4 cells to FAU monophosphate (FAUMP), converted to its methylated form, 5-methyl-FAUMP (FMAUMP), and incorporated into DNA. These prior observations suggested that FAU would be an appropriate prototype for testing the cytotoxic potential of TS-activated prodrugs. It is to be understood that the former study produced data for different purposes and does not directly address the present discovery. To demonstrate the validity of the present concept, the inventors: (1) determined that TS is the enzyme which catalyzed the methylation; (2) examined the net formation rates of methylated species in a variety of cells; and (3) correlated the net formation rates of methylated species with cytotoxic effects.
Among pyrimidine nucleosides, 2′-deoxyuridine (dUrd) analogues are less toxic than their corresponding thymidine (dThd) analogues as indicated by Kong XB, Andreeff M, Fanucchi M P, Fox J J, Watanabe K A, Vidal P, Chou T C, in “Cell Differentiation Effects of 2′-Fluoro-1-beta-D-arabinofuranosyl Pyrimidines in HL-60 Cells.”
Leuk Res,
1987;11:1031-9. The present inventors theorized that following entry into the cell and phosphorylation, an analogue of dUrd would serve as a selective prodrug if TS can methylate it to generate the corresponding dThd analogue. Thus, tumors which are resistant to TS inhibitors, because of high levels of TS, would be particularly sensitive to these deoxyuridine (dUrd) analogues, because they would be more efficient in producing the toxic thymidine (dThd) species. This strategy is completely novel, since it is entirely different from all prior approaches towards TS as an antitumor target. Contrary to previous research and clinical studies which are directed towards the inhibition of TS in order to shrink tumors, the present invention utilizes TS to activate uridine analogue prodrugs into the more toxic thymidine analogues to reduce or inhibit tumor cells, especially tumor cells which are inherently resistant to or develop resistance to existing therapies. The present invention is additionally highly complementary to all prior approaches towards inhibition of TS as an antitumor target.
Further, because success of therapy with drugs such as FAU or its analogues is related to extent of incorporation into DNA, the analysis of DNA can provide diagnostic information regarding the optimal therapy for a tumor. Thus, by examining a biopsy specimen of tumor, or by externally imaging tumors, it can be predicted whether therapy with FAU or related compounds would be successful, or whether alternate therapy should be used.
In addition to assessing tumor therapy, there are a variety of other medical circumstances in which it is important to determine the proliferation rate (growth) of cells within a particular tissue in the body. These include: assessment of bone marrow function (e.g., after transplantation and/or stimulation with growth factors), regeneration of the liver following surgery or injury, and expression of enzyme function following gene therapy.
Traditional approaches to determine growth rate have been invasive; i.e., have required obtaining a biopsy from the patient. In addition to the discomfort and risks associated with biopsy procedures, only a small sample of tissue is obtained. Thus, biopsies car
Anderson Lawrence
Collins Jerry M.
Katki Aspandiar G.
Klecker Raymond W.
Haddaway Keith G.
Riley Jezia
The United States of Americas as represented by the Department o
Venable LLP
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