Combination of G-CSF with a chemotherapeutic agent for stem cell

Details Combination of G-CSF with a chemotherapeutic agent for stem cell Combination of G-CSF with a chemotherapeutic agent for stem cell

1998-11-12

2000-12-19

Mertz, Prema

Drug, bio-affecting and body treating compositions

Lymphokine

514 2, 514 8, 514 76, 514 54, 514110, 514114, A61K 3819, A61K 31675

Patent

active

061624276

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the novel use of G-CSF and a chemotherapeutic agent or a combination of chemotherapeutic agents to produce a pharmaceutical preparation for enhanced mobilization of hematopoietic stem cells in the treatment of diseases requiring peripheral stem cell transplantation as is the case, e.g., in high-dosage chemotherapy or bone marrow ablation by irradiation. In addition, the invention is directed to a pharmaceutical packaging unit containing G-CSF, chemotherapeutic agent(s) and informational instructions regarding the application of the G-CSF and the chemotherapeutic agent or the combination of chemotherapeutic agents for enhanced mobilization of hematopoietic stem cells prior to the onset of a corresponding therapy.
The use of high-dosage chemotherapy or bone marrow ablation by irradiation requires subsequent incorporation of hematopoietic stem cells into the patient, in which case recovery of such cells is required.
In the methods of peripheral stem cell recovery (e.g., in leukopheresis), the mobilization of bone marrow stem cells has a crucial influence on the efficiency of these methods. At present, 2-3 leukophereses are required for successful peripheral stem cell transplantation, resulting in considerable stress for the patients.
The success of treatment crucially depends on the mobilization of the bone marrow stem cells, the subsequent return of which permitting to achieve reconstitution of a functioning hematopoietic system.
Numerous substances capable of effecting such a mobilization are known, e.g., G-CSF (granulocyte colony stimulating factor).
Some chemotherapeutic agents are also known to possess the ability of mobilizing bone marrow stem cells (Richman et al., Blood, Vol. 47, No. 6. 1031 (1976)).
Various documents also describe the combination of G-CSF with other active substances. Thus, combined treatments using antibiotics are known from EP-A-0,648,501 and WO-A-95/28178. The U.S. Pat. No. 5,422,105 reports the combination with one or more antimicrobial substances such as antiviral, antifungal or antibacterial agents in order to enhance the effect of a CSF-1 therapy. In addition, there have been investigations on the use of G-CSF in association with high-dosage chemotherapies in autologous bone marrow transplantations (Lymphokine Cytokine Res. (1994), 13(6), 383-90; and Leukemia and Lymphoma (1995), 19(5-6), 479-84).
In other investigations related to bone marrow transplantations, Shirota et al. have determined that cyclophosphamide which is known as cytostatic agent facilitates the permeability of the endothelial barrier for stem cells (Exp. Hematol. 19, 369-373 (1991)).
As the required number of leukophereses is extremely stressing for the patient in the run-up to the treatment of particular diseases, e.g., in preparing a myeloablative or myelotoxic therapy, the invention was based on the object of achieving a superior yield of stem cells or a decrease in the number of leukophereses via enhanced mobilization of stem cells.
Surprisingly, it has now been found that an unexpectedly high stem cell concentration in blood can be achieved when administering G-CSF in combination with a chemotherapeutic agent (chemotherapeutic agents).
Therefore, the invention is directed to the use of G-CSF and a chemotherapeutic agent or a combination of chemotherapeutic agents to produce a pharmaceutical preparation for enhanced mobilization of hematopoietic stem cells in the treatment of diseases requiring peripheral stem cell transplantation, wherein G-CSF and the chemotherapeutic agent are present formulated in separate administration forms, so that they can be taken out separately and administered successively according to the optimum application regimen. According to the invention, it is preferred to apply the G-CSF prior to the onset of the administration of chemotherapeutic agents in order to enhance the mobilization of hematopoietic stem cells.
The combined use according to the invention of G-CSF and chemotherapeutic agent relates to all those diseases requiring recovery of st

REFERENCES:
Neben et al. Blood, vol. 81, No. 7, 1993, pp. 1960-1967, Apr. 1993.

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