Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1999-12-02
2003-06-03
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S198100, C514S002600, C514S012200, C530S350000, C530S399000
Reexamination Certificate
active
06572851
ABSTRACT:
TECHNICAL FIELD
The present invention relates to drugs for relieving drug-induced nephropathy and hepatitis.
BACKGROUND ART
The use of drugs for therapeutic and/or diagnostic purposes has increased year by year, and the drugs used have diversified. These drugs can provide us significant benefits but can also cause substantially harmful effects, especially to kidneys, due to their specific functions described below.
Kidneys weigh less than one percent of the total body weight. From a physiological viewpoint, 25 percent of the total cardiac output flows into the kidneys; 150 liters of primitive urine, up to 50 times the total blood plasma, is filtered through glomeruli per day; and final urine is made by reabsorption, secretion, and metabolism through uriniferous tubules variable in structural and functional heterogeneity. Thus, drugs or their metabolites in blood always circulate, and these substances are concentrated and metabolized in kidneys. Consequently, various highly concentrated metabolites, including original drugs, are distributed in kidneys. Kidneys are likely to be frequently and intensively exposed to drugs. Four types of drugs may induce nephropathy: antimicrobial agents, nonsteroidal agents, contrast agents, and antitumor agents.
The liver can also be easily damaged by drugs. Drug-induced hepatopathy is classified by its onset mechanism into toxic hepatopathy caused by direct attack of drugs or their intermediate metabolites to the liver, and allergic hepatopathy caused by allergic response, type IV delayed allergic response in which T cells are involved. Drug-induced hepatitis is caused by, most frequently, antibiotics, followed by drugs for the central nervous system, drugs for circulatory organs, antitumor agents, hormonal agents, diagnostic agents, etc.
Attempts have been made to relieve drug-induced disorders by using &ggr;-globulin, cytochrome C, adenine, SH compounds, vitamin B group, etc., but they are not sufficiently effective. It is very important to clinically cure drug-induced disorders (side effects) because of the interruption of the treatment and the importance of patients' quality of life (Q.O.L.).
DISCLOSURE OF THE INVENTION
An objective of the present invention is to drugs that effectively relieve or suppress disorders induced by various drugs, especially by antitumor agents.
The inventors have focused on the facts that proteins belonging to the midkine (MK) family such as midkine (MK) and pleiotrophin (PTN) are growth and differentiation factors with multiple functions. The functions include 1) elongation of neurite, 2) activation of fibrinolytic system, 3) strong expression in human cancerous areas, and 4) cure of wounds. Numerous studies have been performed on such proteins in order to find novel pharmaceutical effects.
Midkine was discovered as a product of the gene whose expression was induced in the early stage of the differentiation process with retinoic acid in mouse embryonic tumor cells (Kadomatsu, K. et al., Biochem. Biophys. Res. Commun., 151: 1312-1318, 1988). Pleiotrophin was discovered in the brain of a newborn rat as a heparin-binding protein with neurite elongation ability (Rauvala, H., EMBO J., 8: 2933-2941, 1989). Midkine and Pleiotrophin form a novel class of growth and differentiation factors as heparin-binding proteins. They exhibit 45% homology and are collectively called the MK family (Muramatsu, T., Int. J. Dev. Biol., 37: 183-188, 1993; Muramatsu, T., Develop. Growth & Differ. 36(1): 1-8, 1994). Midkine and Pleiotrophin each exhibits a specific expression pattern in development processes, and is expected to be involved in important physiological activation in differentiation.
The inventors found that MK inhibits cell death caused by antitumor agents in vitro and that MK gene relieves disorders induced by an antitumor agent from the results of an experiment in which an antitumor agent was administered to knockout mice in which MK gene was functionally destroyed. The inventors also found that administering MK or PTN to wild mice relieves the disorders caused by antitumor agents, to complete the invention. The present invention encompasses each invention described in the claims.
In this invention, knockout mice provided an opportunity to investigate how MK gene in the living body fights against disorders caused by drugs and to analyze how each knockout mouse responds to the forced administration of MK at the individual level. Details of MK's function and mechanism are presently not clear. If MK functions as a trigger protein for the functional cascade of cytokines or growth factors, a very small amount of MK is presumably needed, and the use of knockout mice becomes more important. Recently, a cell surface receptor specifically binding to MK with high affinity (molecular weight 250+kDa) has been discovered. Its characteristics imply that autocrine stimulated by MK in tumor cell proliferation could be mediated by the receptor and would activate the JAK/STAT pathway (Edward, A. R. et al., J. Biol. Chem.
273: 3654-3660, 1998).
To clarify the relationship between MK and ontogenesis, homozygous MK gene-knocked out mice in which parts of exon 2 and exon 3 are damaged as illustrated in
FIG. 1
were prepared (Biochemistry 7, Heisei 8: Volume 68, pp. 1239, 4-P-1244). Those knockout mice did not die during the fetal period and weighed significantly less than heterozygous or wild types (Biochemistry 7, Volume 68, pp. 1239, 4-P-1244, 1996).
Antitumor agents were administered to the knockout mice (simply referred as knockout mice) and wild mice. Survival rate, blood urea nitrogen (BUN) level, and creatinine level of each mouse were compared as indices of disorders after the administration to monitor the ability of MK gene in the living body to relieve disorders caused by antitumor agents. BUN and creatinine levels can be used as indices of functional disorders in kidneys because urea is accumulated in blood due to the reduced renal excretory ability.
In this invention, cisplatin was administered to the knockout mice and wild mice, then BUN level and survival rate were compared. The BUN level of the knockout mice were significantly higher than that of the wild mice. The survival rate of the knockout mice also differed significantly from that of wild mice. The death rate of knockout mice increased by the seventh day after the administration. The rate of abnormal BUN levels in knockout mice that had been forcedly administered MK was significantly lower than that in the group that had been administered physiological saline by the third day after the administration. The effectiveness of MK in suppressing renal cell disorders caused by cisplatin was confirmed by conducting an experiment in vitro using human infantile renal cancer cell lines. An experiment using the wild mice revealed that MK relieved acute hepatopathy due to carbon tetrachloride, and that both PTN and MK effectively suppress nephropathy caused by cisplatin.
These results indicate that proteins of this invention belonging to the MK family effectively relieve or suppress drug-induced nephropathy and hepatopathy.
MK protein (simply referred to as MK) used as an effective ingredient of the pharmaceutical composition of the invention is described in the following references (human MK gene, unexamined published Japanese patent application (JP-A) No. Hei 5-91880; sequences of the human MK gene and protein, JP-A No. Hei 6-217778; MK protein, JP-A No. Hei 5-229957; Muramatsu, T., Develop. Growth & Differ. 36(1), 1-8, 1994). PTN protein used as an effective ingredient of the pharmaceutical composition of the invention is described in the following references (Muramatsu, T., Develop. Growth & Differ. 36(1), 1-8, 1994; Kurtz, A. et al., Critical Reviews in Oncogenesis, 6(2):151-177, 1995).
FIGS. 11 and 12
show the amino acid sequence of PTN and MK proteins, respectively. The proteins belonging to the MK family and used as effective ingredients of the pharmaceutical composition of this invention include natural proteins derived from humans, mice, or other mammals, o
Ikematsu Shinya
Kadomatsu Kenji
Muramatsu Takashi
Oda Munehiro
Sakuma Sadatoshi
Bunner Bridget E.
Kemmerer Elizabeth
Saliwanchik Lloyd & Saliwanchik
Takashi Muramatsu
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