Anti-cancer products for treating cystic fibrosis

Details Anti-cancer products for treating cystic fibrosis Anti-cancer products for treating cystic fibrosis

1999-11-29

2003-10-21

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

Reexamination Certificate

active

06635627

ABSTRACT:

This Application is a 371 of PCT/FR98/01074 filed May 28, 1998, which claims priority from France 97/06667 filed May 30, 1997.
The present invention relates to a novel approach for treating cystic fibrosis which involves chemotherapy, in particular anticancer chemotherapy.
Cystic fibrosis is a genetic disease which is expressed in particular in the lungs and which is due to a defect in the gene encoding the CFTR (standing for “Cystic Fibrosis Transmembrane Conductance Regulator”) protein, which is a protein which is able to participate directly or indirectly in the transport of chloride ions across the cell membranes.
In a general way, the CFTR protein belongs to the ABC (standing for “ATP Binding Cassette”) transporter family, which is a very extensive family of proteins whose members are found both in eukaryotes and in prokaryotes. In general, these proteins are active transporters which hydrolyze ATP in order to supply the chemical potential which is required for their transport function. Thus, in eukaryotes, they transport various types of molecule across the cell membranes. Molecules which are capable of being transported and which may be mentioned include ions, vitamins, peptides, sugars and medicinal substances or other drugs. Their overall organization has common features: they generally comprise a transmembrane (TM) region, which is involved in selecting the chemical entity to be transported, and a nucleotide-binding domain which hydrolyzes the ATP in order to supply the chemical potential which is required for the transport (NBF standing for “Nucleotide Binding Fold”).
The genes which encode these proteins are often derived from the fusion of two genes of analogous structure.
The structure of the corresponding proteins is then generally as follows:
(TM1)-(NBF1)-(TM2)-(NBF2)
The CFTR protein constitutes a 1480-amino-acid-containing member of a subfamily of the ABC transporter family termed the MRP/CFTR subfamily. In addition to the CFTR protein, this subfamily contains the human MRP protein. Specifically, the two proteins exhibit a sequence similarity of approximately 50%. The MRP (standing for “Multi-drug Resistance associated Protein”) is known to be involved in phenomena of multiresistance to the medicaments which are used in cancer chemotherapy (M. Dean, R. Allikmets, Current Opinion in Genetics & Development, 5, 779-785, 1995). The CFTR protein is also structurally very close to another member of the MRP/CFTR subfamily, i.e. the protein YCF1 (standing for “Yeast Cadmium Resistance Factor 1”), which confers on the yeast Saccharomyces cerevisiae the phenotype of resistance to cadmium ions (Tommasini et al., PNAS, 93, 6743-6748, 1996). As well as their similarity in structure, the MRP and YCF1 proteins function in a similar way: they export molecules and ions in the form of their adducts with glutathione (G. J. Zaman et al., PNAS, 92, 7690-7694, 1995).
The CFTR protein also displays not insignificant structural similarities with the yeast STE6 protein, which transports the pheromone “factor a” in the yeast Saccharomyces cerevisiae (J. L. Teem et al., Cell, 73, 335-346, 1993) and with the human MDR (standing for “Multi-drug Resistance Protein”) protein, which is known, like MRP, to be involved in the phenomena of multiresistance to anticancer medicaments. The human MDR protein and the STE6 protein belong to another subfamily of ABC transporters, termed the MDR/TAP subfamily.
Thus, the general adherence of the CFTR protein to the ABC transporter family, and its function of transporting chloride ions, are now well known.
In a patient suffering from cystic fibrosis, the CFTR protein is mutated. While more than 600 mutations have been recorded, the mutation involved is, in approximately 70% of cases, the deletion of a phenylalanine in position 508 in the NBF1 part (&Dgr;F508) of the overall structure of the protein. It appears that this mutation results in a defect in the folding of the protein which is then destroyed within the cell without completing its post-translational maturation (Riordan J. R., Rommens J. M., Kerem B. S., Alon N., Rozmahel R., Grzelczack Z., Zielenski J., Lok S., Plavic N., Chou J. L., Drumm M. L., Iannuzzi M. C., Collins F. S., Tsui L. C. (1989) Science. 245, 1066-1072). The absence of a mature or functional CFTR protein leads to a defect in the secretion of chloride ions. The so-called “sweat” test, which measures the secretion of chloride ions, was, moreover, developed in 1953 and remains indispensable for diagnosing cystic fibrosis.
Up to now, attempts have been made to treat cystic fibrosis by gene therapy, by means of developing systems for administering to patients a nucleic acid which encodes the wild-type CFTR protein and which is transported either by viruses or by cationic lipids. Attempts have been made to administer such a DNA/cationic lipid complex to lungs of mice by the intratracheal route (Yoshimura et al., Nucleic Acid Research, 20 :3233-3240, 1992) or by means of an aerosol (Stribling et al., Proc. Natl. Acad. Sci. 89:11,277-11,281, 1992). It has also been observed that administering the CFTR-encoding gene, in a complex together with cationic lipids, to a mouse model suffering from cystic fibrosis had the effect of correcting the defect in the function of the chloride ion channel (Hyde et al., Nature 362:250-255, 1993).
Thus, the therapeutic approaches which are currently envisaged in the case of cystic fibrosis are solely aimed at the genetic defect (mutation in the gene encoding the CFTR protein), which they are endeavoring to correct. They link the efficacy of the treatment to the re-establishment of the only chloride-ion channel function which is exerted by a functional CFTR protein.
However, even though the defect in the transport of chloride ions is indeed a clinical manifestation of cystic fibrosis, other manifestations have still not been fully explained.
Thus, as an example, the organs which are chiefly affected in cystic fibrosis are those in which glutathione is secreted, in particular the liver, or those in which detoxification mechanisms are likely to involve glutathione (lungs, intestine, colon).
Furthermore, it has been noted that the inflammatory reaction is excessive in patients suffering from cystic fibrosis. A chronic inflammation of the airways is often observed in these patients. When this occurs, a very high number of neutrophilic granulocytes is present in the airways of the patients, even when there is no detectable infection. It is possible that this inflammation precedes the appearance of the chronic infection. This influx of neutrophilic granulocytes results in a massive release of free radicals and hyperoxides in the cells of the airways of the patients. Now, it is known that exocellular and intracellular glutathione plays a central role in the control of the inflammatory reaction by protecting the cells from attack by these oxidizing agents. However, this protection appears to be impaired in patients suffering from cystic fibrosis. It would therefore appear that cystic fibrosis prevents glutathione from playing its customary role.
Studies performed on the family of ABC transporter proteins have demonstrated their relative versatility. Even though each of the proteins possesses its own function, they appear to display a shared mode of operation which enables them to undertake shared functions. For example, it has been demonstrated in vitro that the human MRP protein is able to act as a substitute for YCF1 in yeast and to undertake the function of detoxifying cadmium in this organism (Tomassini et al., PNAS, 93, 6743-6748, 1996). It can also act as a substitute for the STE6 protein in yeast in order to undertake the transport of factor a in this organism (J. L. Teem et al., Cell, 73, 335-346, 1993). Similarly, an STE6 chimeric protein, in which the CFTR NBF1 domain has been substituted for the STE6 NBF1 domain, is functional and efficiently transports factor a (J. L. Teem et al., Cell, 73, 335-346, 1993). Finally, it would appear that, in vivo, the genes which encode the CFTR, MDR and MRP proteins are

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