[Rich66]

PATENT: Ok...2002 filing, 2009 publication???? At least suggestion the researcher lives..maybe. Anyone live in Pikesville, Maryland?


http://www.freepatentsonline.com/7547673.html
Title:
Therapeutics for cancer using 3-bromopyruvate and other selective inhibitors of ATP production

United States Patent 7547673

Abstract:
The present invention relates to methods of treating a cancerous tumor using selective inhibitors of ATP production. The present invention also relates to pharmaceutical preparations comprising such inhibitors and methods for administering them intraarterially directly to a tumor, as well as methods for identifying compositions that selectively inhibitor ATP production for use in the invention.

Inventors:
Ko, Young He (Pikesville, MD, US)
Geschwind, Jean-francois H. (Potomac, MD, US)
Pedersen, Peter L. (Columbia, MD, US)


Application Number:
10/243550

Publication Date:
06/16/2009

Filing Date:
09/13/2002

View Patent Images:
Download PDF 7547673 PDF help

Export Citation:
Click for automatic bibliography generation

Assignee:
The Johns Hopkins University (Baltimore, MD, US)


Primary Class:
514/34

Other Classes:
514/1, 514/171, 514/557

International Classes:
A61K38/16; A61K38/21

Field of Search:
604/510, 514/563, 514/1, 514/562, 514/922, 514/893, 604/508, 604/507, 514/908, 514/274, 514/557, 514/440

US Patent References:

6312662	Prodrugs phosphorus-containing compounds	November, 2001	Erion et al.	424/9.1
6448030	Method for predicting the efficacy of anti-cancer drugs	September, 2002	Rust et al.	435/29
6670330	Cancer chemotherapy with 2-deoxy-D-glucose	December, 2003	Lampidis et al.	514/23
20010046997	Allosteric inhibitors of pyruvate kinase	November, 2001	Abraham et al.	514/249
20020006915	Use of COX-2 inhibitors to treat sepsis, complications thereof, and EP receptor modulation	January, 2002	Mack Strong et al.	514/44
20020068711	Arrest of proliferation of highly glycolytic tumors	June, 2002	Pedersen et al.	514/44
20030018166	Structure of isocitrate lyase enzyme from mycobacterium tuberculosis and inhibitory agents to combat persistent infection	January, 2003	Sacchettini et al.
20030139331	Treatment of cancer by reduction of intracellular energy and pyrimidines	July, 2003	Martin et al.
20040029826	Compounds for targeting hepatocytes in vivo	February, 2004	Sokoloff et al.
20040167079	Treatment of cancer with 2-deoxyglucose	August, 2004	Tidmarsh
20040167196	Treatment of benign prostatic hyperplasia	August, 2004	Tidmarsh
20060154867	Compounds for targeting hepatocytes	July, 2006	Sokoloff et al.

Other References:
Fiebig et al., “Relevance of Tumor Models for Anticancer Drug Development”, Contrib. Oncol. Basel. Karger, vol. 54, pp. 109-120 (1999).
Chemical Abstracts 124:193528, “Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil”, Kerr et al (1995).
Kerr et al., “Phase I Clinical and Pharmacokinetic Study of Leucovorin and Infusional Hepatic Arterial Fluorouracil”, Journal of Clinical Oncology, vol. 13, No. 12, pp. 2968-2972 (Dec. 1995).
Lin et al, Effects of 90Y-Microspheres on Liver Tumors: Comparison of Intratumoral Injection Method and Intra-Arterial Injection Method, Nov. 2000, The Journal of Nuclear Medicine, vol. 41, No. 11, p. 1892.
Kerr et al, Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial flurouracil, Dec. 1995, Journal of Clinical Oncology, vol. 13, No. 12, p. 2968.
Arafat et al.; “Toxicities Related to Intraarterial Infusion of Cisplatin and Etoposide in Patients with Brain Tumors”, Journal of Neuro-oncology 42: 73-77, (1999).
Bar et al.; “Sorbitol Removal by the Metastatic Liver: A Predictor of Systemic Toxicity of Intra-arterial Chemotherapy in Patients with Liver Metastases”, Journal of Hepatology 30: 1112-1118, (1999).
Geschwind et al.; “Novel Therapy for Liver Cancer: Direct Intraarterial Injection of a Potent Inhibitor of ATP Production”, Cancer Research, 62:3909-3913, (2002).
Gobin et al.; “Intraarterial Chemotherapy for Brain Tumors by Using a Spatial Dose Fractionation Algorithm and Pulsatile Delivery”, Radiology 218(3): 724-732, (Mar. 2001).
Ko et al., “Metabolic Properties of the Rabbit VX2 Tumor Model Following Liver Implantation: Role for Hexokinase”, Cancer Research 42: 519(#2796), (Mar. 2001).
Ko et al.; “Glucocatabolism in the Rabbit VX2 Tumor Model for Liver Cancer: Characterization and Targeting Hexokinase”, Cancer Letters 173: 83-91, (2001).
Kostron et al.; “Photodynamic Treatment of Malignant Brain Tumors”, Jg 102, Heft 18 : 531-535, (Sep. 28, 1990).
Mathupala et al.; “Glucose Catabolism in Cancer Cells”, The Journal of Biological Chemistry, 276(46): 43407-43412, (Nov. 16, 2001).
Pedersen et al.; “Mitochondrial Bound Type II Hexokinase: a Key Player in the Growth and Survival of Many Cancers and an Ideal Prospect for Therapeutic Intervention”, Biochimica and Biophysica Acta 1555: 14-20, (2002).
Soulen et al.; “Intraarterial Chemotherapy with Limb-sparing Resection of Large Soft-tissue Sarcomas of the Extremities”, JVIR, 3: 659-663, (1992).
Wang et al.; “Isolated Lower Extremity Chemotherapeutic Infusion for Treatment of Osteosarcoma: Experimental Study and Preliminary Clinical Report”, J. Vasc. Interv. Radiol. 12: 731-737, (2001).
Johns Hopkins Medical Institutions Office of Communications and Public Affairs “Energy Blocker May Be Potential Liver Cancer treatment”, www.hopkinsmedicine.org/press/2002/July/020715.htm.
Pederson, P., ““Energy Blocker” Kills Big Tumors in Rats”, Audio File—Johns Hopkins Medicine, Office of Corporate Communications, Oct. 14, 2004.
Ko et al., “Advanced Cancers: Eradication in All Cases Using 3-bromopyruvate Therapy to Deplete ATP⋆, ⋆⋆”, Press Release, Nov. 5, 2004.
Ko et al., “Advanced Cancers: Eradication in All Cases Using 3-bromopyruvate Therapy to Deplete ATP⋆, ⋆⋆”, BBRC, 324(1):269-275, (2004).


Primary Examiner:
Marschel, Ardin

Assistant Examiner:
Vakili, Zohreh

Attorney, Agent or Firm:
Russell, Esq. Hathaway P.
Foley Hoag LLP


Parent Case Data:
RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119(e) to Provisional Application Ser. No. 60/318,710, filed Sep. 13, 2001, the content of which is incorporated by reference in its entirety herein.


Claims:
We claim:

1. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor an effective amount of a 3-halopyruvate or a salt thereof delivered by transcatheter hepatic intraarterial injection into the liver.

2. The method of claim 1, wherein the 3-halopyruvate is 3-bromopyruvate.

3. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor a therapeutically effective amount of a 3-halopyruvate or a salt thereof and fluorouracil delivered by transcatheter hepatic intraarterial injection into the liver.

4. The method of claim 1, wherein the 3-halopyruvate or salt thereof is provided in a sustained-release formulation.

5. The method of claim 3, wherein the 3-halopyruvate is 3-bromopyruvate.

6. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor delivered by transcatheter hepatic intraarterial injection into the liver an effective amount of a compound represented by formula: wherein, independently of each occurrence: X represents a halide; R₁ represents OR, H, N(R″)2, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, or C6-C12 heteroaryl; R″ represents H, C1-C6 alkyl, or C6-C12 aryl; R represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′; and R′ represents H, C1-C20 alkyl or C6-C12 aryl, or a salt thereof.

7. The method of claim 6, wherein the halide is bromide.

8. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor delivered by transcatheter hepatic intraarterial injection into the liver an effective amount of a compound represented by formula: wherein, independently of each occurrence: X represents a halide; R₁ represents OR, H, N(R″)2, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, or C6-C12 heteroaryl; R″ represents H, C1-C6 alkyl, or C6-C12 aryl; R represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′; and R′ represents H, C1-C20 alkyl or C6-C12 aryl, or a salt thereof and administering fluorouracil to said subject.

9. The method of claim 8, wherein the halide is bromide.

10. A method of treating a liver tumor that has metastasized within the liver of a subject an effective amount of a 3-halopyruvate or a salt thereof delivered by transcatheter hepatic intraarterial injection into the liver.

11. The method of claim 10, wherein the 3-halopyruvate is 3-bromopyruvate.

12. The method of claim 1, wherein the 3-halopyruvate is administered directly to the blood supply of the tumor without embolization of the tumor.

13. The method of claim 1, consisting of administering to a subject having a liver tumor an effective amount of a 3-halopyruvate or a salt thereof delivered by transcatheter hepatic intraarterial injection into the liver.



Description:
GOVERNMENT SUPPORT

The subject invention was made in part with support from the U.S. Government under a grant (CA 80118) from the National Institutes of Health. Accordingly, the U.S. Government has certain rights in this invention.
BACKGROUND OF THE INVENTION

One of the most common, profound, and intriguing phenotypes of highly malignant tumors, known for more than six decades, is their ability to metabolize glucose at high rates to synthesize high levels of ATP. Under aerobic conditions more than half of the ATP produced in such tumor cells is derived via glycolysis, in sharp contrast to normal cells, where this value is usually less than 10% and oxidative phosphorylation is the predominant method for ATP generation. Under hypoxic (low oxygen tension) conditions, frequently present within tumors, the already high glycolytic rate may double, allowing the tumor cells to thrive while neighboring normal cells become growth deficient. This is a characteristic of both animal and human tumors including those derived from brain, breast, colon, liver, lung, and stomach. In each, a close correlation exists among the degree of de-differentiation, growth rate, and glucose metabolism, where the most de-differentiated tumors exhibit the fastest growth and the highest glycolytic rate. In fact, this unique phenotype is used clinically worldwide in Positron Emission Tomography (PET) to detect tumors, assess their degree of malignancy, and in some, cases even predict survival time.
Despite the commonality of the high glycolytic phenotype and its widespread use clinically as a diagnostic tool, it has not been exploited as a major target for arresting or slowing the growth of cancer cells because the underlying molecular basis of the high glycolytic phenotype is not completely characterized. It had long been suspected to involve some type of mitochondrial glycolytic interaction. Recent experiments have demonstrated a requirement for an overexpressed mitochondrially bound form of hexokinase, now identified as Type II hexokinase.
Liver cancer, in particular hepatocellular carcinoma (hepatoma), is one of the most common fatal cancers in the world and soon may reach epidemic levels due to increased incidences of virally-induced hepatitis. Among its numerous victims are not only those with primary tumors that develop directly in the liver but those with secondary tumors that frequently arise in this critical metabolic organ as a result of metastasis from other tissues, e.g., the colon. Unfortunately, traditional treatment options are limited by poor response rates, severe toxicities, and high recurrence rates resulting in a mean survival time of about 6 months. Hepatomas are known to exhibit a high glucose catabolic rate, and where examined carefully, to contain elevated levels of hexokinase bound to their mitochondria. Moreover, in the AS-30D hepatoma, the most extensively studied tumor in this class, it has been shown also that the gene for hexokinase is amplified and that the mRNA levels are markedly elevated. Therapeutic methods directed at inhibition of metabolic activity in hepatoma are limited by the fact that a potent agent directed at any of the metabolic enzymes such as hexokinase in the tumor will also target the patient's metabolic enzymes, resulting in severe toxicity. Thus, less potent, but very specific agents such as antisense molecules, have been used to inhibit tumor metabolic activity.
In recent years, the VX2 tumor, an epidermoid rabbit tumor induced by the Shope papilloma virus, has shown promise as a model system for studying hepatoma. The VX2 tumor grows well when implanted in the rabbit's liver, where it takes on growth properties and a vascularization system similar to many human liver tumors. Thus, it is possible via the method known as transcatheter chemoembolization to deliver anticancer agents directly to the implanted tumor via the hepatic artery. In addition, it has been shown that when delivery is made using certain oils the mixture preferentially localizes in the tumor rather than in the surrounding liver tissue. This is important as it may allow for the targeting of exceptionally potent cancer killing agents directly to the tumor for brief periods of time thus minimizing damage to the surrounding liver tissue and toxicity to the host. The energy metabolism of the VX2 tumor requires further characterization in order to determine to what extent it mimics a rapidly growing hepatoma (e.g. exhibits a high glycolytic phenotype, expresses mitochondrially bound hexokinase, etc.).
SUMMARY OF THE INVENTION

The present invention provides in part therapeutic compositions comprising and methods of treating cancer using 3-bromopyruvate and other selective inhibitors of ATP production.
In a preferred embodiment, the invention further provides inhibitors of ATP production represented in general formula:
X—CH2—CO—COOH,


Related delivery formulation patent:
http://www.freshpatents.com/Composit...0070203074.php