Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-03-07
2003-07-08
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S051000, C514S052000, C514S974000
Reexamination Certificate
active
06589941
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The occurrence of “drug resistance” is the main reason for failure in cancer chemotherapy. Tumors which initially react sensitively to cytostatic agents very frequently recover after a certain treatment time and then are resistant to the effects of various types of antineoplastic drugs. Although the problem of “drug resistance” has been known since 1948 (the year when cancer therapy with cytostatic agents began), until now no way has been known of preventing the formation of resistance.
A characteristic of all highly resistant tumors and cell strains investigated to date is the amplification (multiplication) of a small group of genes. As a result of this DNA or gene amplification, an increased expression of these genes is exhibited, which can lead to resistance to the drug. As a result of this DNA amplification an increased expression of various genes occurs. Protective proteins which serve to shuttle toxins out of the cell can thus be formed in increased quantities (e.g., P-glycoprotein). This effect is also known as “multi-drug resistance” (MDR).
In addition to MDR, the degree of amplification of certain genes, especially certain oncogenes, correlates with the degree of malignancy. Thus, the chances of survival with an amplification of ERVV2, RASKI, INT3, HST1, MYC and KSRAM in stomach cancer are very poor. See Hirohasi, S., and Sugimura, T., “Genetic Alterations in Human Gastric Cancer,
Cancer cells
(Cold Spring Harbor), 3:49-52 (1991). The chances of survival with an amplification of and ERBB2 and MYC in ovarian carcinoma are also very poor. See Sasano, H., Garrett, C. T., Wilkinson, D. C., Silverberg, S., Comerford, J., and Hyde, J., “Protooncogene Amplification and Tumor Ploidy in Human Ovarian Neoplasm”,
Hum. Pathol
., 21:382-391 (1990).
In breast cancer, the amplification of MYC correlates with the progress of the disease. See Borg, A., Baldetorp, B., Fernö, M. Olsson, H., and Sigurdsson, H., “C-myc Amplification is an Independent Prognostic Factor in Postmenopausal Breast Cancer”,
Int. J. Cancer
, 51:687-691 (1992). Likewise, in breast cancer, the coamplification of INT2 and HST1 correlates with the progress of the disease. See Borg, A., Sigurdsson, H., Clark, G. M., et al., “Association of INT2/HST1 Coamplification in Primary Breast Cancer with Hormone-Dependent Phenotype and Poor Prognosis”,
Br.J.Cancer
, 63:136142 (1991).
The amplification of ERBB2 and EGFR is linked to a poor prognosis. See Descotes, F., Pavy, J. -J., and Adessi, G. L., “Human Breast Cancer: Correlation Study Between HER-2
eu Amplification and Prognostic Factors in an Unselected Population”,
Anticancer Res
., 13:119-124 (1993) and Klijn, J. G. M., Berns, P. M. J. J., Schmitz, P. I. M., and Foekens, J. A., “The Clinical Significance of Epidermal Growth Factor Receptor (EGF-R) in Human Breast Cancer: A Review on 5232 Patients”,
Endocr.Rev
., 13:3-17 (1992).
In esophageal cancer, the coamplification of HST1 and INT2 correlates with the degree of metastasis. See Tsuda, T., Tahara, E., Kajiyama, G., Sakamoto, H., Terada, M., and Sugimura, T., “High Incidence of Coamplification of HST-1 and INT-2 Genes in Human Esophageal Carcinomas”,
Cancer Res
. 49:5505-5508, 1989).
In summary it can be ascertained that by means of chronic treatment with carcinogenic cytostatic agents, the induced gene amplification leads not only to resistance to this treatment, but also to the over-expression of certain oncogenes which control the degree of malignancy.
2. Discussion of Background
A series of substances have been described which counteract the acquired drug resistance. Included are those described in the work of Kennedy on the anti-carcinogenic effects of protease inhibitors. See Kennedy, A. R., “Prevention of Carcinogenesis by Protease Inhibitors”,
Cancer Res
., 54:1999-2005 (1994). These substances can suppress carcinogen-induced gene amplification to almost normal levels. Kennedy observed that radiation-induced gene amplification is suppressed in the same way corresponding with its capacity to suppress radiation-induced transformation, so that a relationship between these two processes can be assumed. In addition, protease-inhibitors act as antagonists of (co-recombinogenic) tumor inducers during the initiation of transformation in vitro. Protease-inhibitors are also described as effective anti-promoters in in vivo experiments. See Troll, W., Klassen, A., and Janoff, A., “Tumorigenesis in Mouse Skin: Inhibition by Synthetic Inhibitors of Proteases”,
Science
(Washington D.C.) 169:1211-1213 (1970).
It is known that verapamil acts against MDR. See Moscow, I. A., and Cowan, K. H., “Multidrug Resistance”, J. Natl. Cancer Inst., 80:14-20 (1988). This “calcium channel blocker” increases the cytotoxicity by increasing the intracellular accumulation of drugs, probably in part due to an effect on P-glycoprotein or other transport proteins. The toxicity of these and similar substances, such as quinidine, reduces their clinical usefulness.
SUMMARY OF THE INVENTION
In view of the foregoing, the present invention provides an effective substance for preventing or reducing resistance formation against treatment with cytostatic agents and provides for a corresponding drug. The present invention provides for a composition for preventing or reducing the formation of resistance in cytostatic treatment, the composition combining at least one 5′ substituted nucleoside with at least one cytostatic agent.
The present invention provides for a method of producing a composition for preventing or reducing formation of resistance in cytostatic treatment comprising combining (E)-5-(2-bromovinyl-)2′-deoxyuridine (BVDU), a salt thereof, or BVDU in protected or in prodrug form with at least one cytostatic agent, which is an anti-carcinogenic agent and which is not 5-fluorouracil.
The present invention also provides for a composition for preventing or reducing the formation of resistance in cytostatic treatment comprising:
(E)-5-(2-bromovinyl-)2′-deoxyuridine (BVDU), a salt thereof, or BVDU in protected or in prodrug form, and
at least one cytostatic agent, which is an anti-carcinogenic agent and which is not 5-fluorouracil, wherein the quantity of BVDU is effective to produce a concentration of 0.02 &mgr;g/ml to 10 &mgr;g/ml in blood.
The composition may also include at least one conventional carrier and may include at least one auxiliary material.
BVDU may be present in an amount effective to produce a concentration of 0.05 &mgr;g/ml to 5 &mgr;g/ml in blood.
Preferably, the at least one cytostatic agent may be selected from one or more of 20 alkaloids, alkylating agents, anti-metabolites, antibiotics, or cisplatin.
The present invention also provides for a method of reducing resistance in cytostatic treatment comprising delivering therapeutically-effective amount of at least one cytostatic agent, which is an anti-carcinogenic agent and which is not 5-fluorouracil, and therapeutically-effective amount of BVDU a salt thereof, or BVDU in protected or in prodrug form.
BVDU may be present in a therapeutically-effective amount, i.e., an amount effective to produce a blood concentration of BVDU from about 0.02 &mgr;g/ml to about 10 &mgr;g/ml. Preferably, BVDU is present in an amount effective to produce a blood concentration of from about 0.05 &mgr;g/ml to about 5 &mgr;g/ml.
The at least one cytostatic agent may be selected from one or more of alkaloids, alkylating agents, antibiotics, antimetabolites, hormonal agonists/antagonists or steroids and combinations.
The alkylating agents may be selected from one or more of bisulfan, carboplatin, cisplatin, melphalan, cyclophosphamide, ifosfamide, chloroambucil, mechlorethamine HCl, carmustine, lomustine, polifeprosan 20 or streptozocin sterile powder.
The antibiotics may be selected from one or more of doxorubicin hydrochloride, bleomycin sulfate, daunorubicin HCl, diactinomycin, daunorubicin citrate, doxorubicin HCl, idarubicin HCl, plicamycin, mitomycin, pentostatin, mitoxantrone, doxorubicin hydrochloride, or valrubicin.
Fahrig Rudolf
Steinkamp-Zucht Angela
Greenblum & Bernstein P.L.C.
Lewis Patrick
Resprotect GmbH
Wilson James O.
LandOfFree
Utilization of 5′ substituted nucleosides for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Utilization of 5′ substituted nucleosides for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Utilization of 5′ substituted nucleosides for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3013641