Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-04-25
2001-12-18
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C424S093600, C514S045000
Reexamination Certificate
active
06331528
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for treatment in gene therapy and use of the specified guanine derivative as the pharmaceutical agent for gene therapy of tumor, restenosis after PTCA and graft vs. host diseases; more specifically, the present invention relates to a method for treatment in gene therapy, comprising the step of administering (administrating) as the pharmaceutical agent for gene therapy, (−)-9-[1′S,2′R-bis(hydroxymethyl)cyclopropan-1′-yl]methylguanine or a derivative convertible to the guanine derivative in animal bodies, into a living subject such as humans; still more specifically, the present invention relates to an use of the guanine derivative as the pharmaceutical agent for gene therapy, wherein the guanine derivative as the pharmaceutical agent is used in combination with the gene used for the gene therapy, which is preferably the gene of an enzyme phosphorylating the guanine derivative, more preferably thymidine kinase gene, particularly the thymidine kinase gene of a virus (for example, herpesvirus).
2. Description of the Related Art
Clinical modalities of the gene therapy of cancer include the following:
1. a modality directly targeting cancer-related genes, comprising introducing cancer suppresser genes such as P53 gene and antisense genes of cancer genes into cancer cells;
2. a modality enhancing immunity against cancer, comprising introducing various cytokine genes and syngenic MHC genes into tumor-infiltrating lymphocytes and cancer cells;
3. a modality introducing suicide genes into cancer cells to permit the cancer cells to be sensitive to drugs, comprising introducing the herpesvirus-thymidine kinase gene (HSV-TK gene) into cancer cells and administering ganciclovir (GCV) as a therapeutic agent of herpesvirus, to kill the cancer cells; and
4. a modality comprising introducing a multi-resistant gene into hematopoietic cells to enhance the resistance against anti-cancer agents and subsequently subjecting the cancer cells to chemical therapies at large doses (see MATSUSHITA Eiki et al., Liver, Gall Bladder and Spleen 34(4): 433-438, 1997).
Clinical protocols using such modalities have been approved for various subjects of cancers, such as melanoma, cerebral tumor, breast cancer, large intestine cancer including colon cancer, lung cancer, ovarian cancer, and kidney cancer. A clinical protocol using the modality described above in 3 has been reported for hepatocellular carcinoma (see Huber, BE, Richards CA, Krenisky TA: Retroviral mediated gene therapy for the treatment of hepatocellular carcinoma: An innovative approach for cancer therapy. Proc. Natl. Acad. Sci. USA 88: 8039-8043, 1991). Recently, a clinical report about cerebral tumor has been issued (see Ram Z. et al., Nat. Med. 3(12), p.1354-1361, 1997).
SUMMARY OF THE INVENTION
1. Problem that the Invention is to Solve
Various methods have been proposed for gene therapies comprising introducing genes into human bodies, but none of the methods is a satisfactory method. Therefore, research works have been promoted about various methods, particularly about pharmaceutical agents therefor, genes therefor and vectors carrying the genes. However, research works about pharmaceutical agents for use in combination with the genes for gene therapies have not made any progress yet. For example, ganciclovir is reported (see S T Clair M H, Lambe C U, Furman P A: Inhibition by ganciclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information. Antimicro. Agents Chemother. 31: 844-849, 1987). Ganciclovir induces the occurrence of bone marrow suppression and reproductive toxicity, which is a factor regulating the administration of ganciclovir. Aciclovir (ACV) of the same nucleoside-type antiviral agent as ganciclovir has been known, but has an extremely poor therapeutic effect.
In such circumstances, the development of a pharmaceutical agent used for gene therapy, having a particularly high safety profile and an excellent therapeutic effect, is desired as an anti-cancer agent.
It is a purpose of the present invention to develop an excellent pharmaceutical agent which can be used for gene therapy, particularly a pharmaceutical agent with highly efficacious effects in human bodies, in particular, from both the respects of pharmaceutical efficacy and safety profile.
2. Means for Solving the Problem
The present inventors have made investigations so as to solve the problem. Consequently, the present inventors have found that by using the compound represented by the following structural formula (1), (−)-9-[1′S,2′R-bis(hydroxymethyl)cyclopropan-1′-yl]methylguanine or a derivative convertible to the compound in animal bodies (sometimes totally abbreviated as “guanine derivative”) as a component of the pharmaceutical agent for gene therapy in combination, preferably with the gene of an enzyme phosphorylating the guanine derivative, particularly with the thymidine kinase gene of a virus, such as herpesvirus, more particularly with the thymidine kinase gene of HSV-1, HSV-2 or VZV as the gene for use, the guanine derivative is phosphorylated, particularly triphosphorylatecl in bodies of animals, such as humans, particularly in cells at a diseased lesion such as tumor cell, to terminate polymerization of DNA chain of which the inhibition is intended and thereby exert cellular toxicity; that the inhibitory action thereof can be exerted on bystander cells; and that the guanine derivative can be used as the pharmaceutical agent for gene therapies of tumor, restenosis after PTCA and graft vs. host diseases. Based on the findings, the present invention has been achieved.
More specifically, the present invention relates to a method for treatment in gene therapy, which comprises administering (administrating) as the pharmaceutical agent for gene therapy (−)-9-[1′S,2′R-bis(hydroxymethyl)cyclopropan-1′-yl]methylguanine or a derivative convertible to the compound in animal bodies (guanine derivative), into a living subject such as humans, which can be used particularly for the therapeutic treatment of tumor, restenosis after PTCA, graft vs. host diseases and the like. Additionally, the method and the pharmaceutical agent for gene therapy used in the present invention encompasses the following inventions.
1. The method described above wherein the gene therapy is for the therapeutic treatment with suicide gene therapy.
The aforementioned gene therapy is the treatment with the pharmaceutical agent for suicide gene therapy.
2. The method described above wherein the treatment is for the therapeutic treatment of humans afflicted with any of tumor, restenosis and graft vs. host diseases.
The treatment is for humans, and therefore the pharmaceutical agent is a therapeutic agent for humans, preferably for treating tumor, restenosis after PTCA, graft vs. host diseases and the like (the term “therapeutic treatment” includes the use of the guanine derivative for therapeutic treatment, amelioration, prevention of exacerbation, prophylaxis, etc.).
3. The method as describe above wherein the pharmaceutical agent of the guanine derivative is for parenteral dosing, particularly intravenous dosing at 0.001 to 10,000 mg/kg per day to humans or for oral dosing at 0.005 to 50,000 mg/kg per day to humans which may be administered thereinto.
4. The method described above wherein the pharmaceutical agent (the guanine derivative) for gene therapy is used in combination with the gene of an enzyme phosphorylating the guanine derivative described above, preferably thymidine kinase gene, more preferably viral thymidine kinase gene.
5. The method described above wherein the gene of an enzyme phosphorylating the guanine derivative is the thymidine kinase gene of herpesvirus (including HSV-1, HSV-2 and VZV).
6. The method described above wherein the thymidine kinase gene is a gene carried on a viral vector to be inserted in a target cell.
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Ajinomoto Co. Inc.
Crouch Deborah
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Woitach Joseph
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