Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1996-04-19
1998-06-23
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
548547, 549271, 549293, 549321, 558248, C07D24324, C07D26106, C07D20740, C07D31304
Patent
active
057707316
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is related to International Application No. PCT/GB94/01610 filed Jul. 27, 1994 and GB 9315494.6 filed Jul. 27, 1993, the priority date of which is claimed.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to prodrugs and their use in the treatment of tumours.
2. Description of the Related Art
The use of prodrugs represents a clinically very valuable concept in cancer therapy since, particularly where the prodrug is to be converted to an anti-tumour agent under the influence of an enzyme that is linkable to a monoclonal antibody that will bind to a tumour associated antigen, the combination of such a prodrug with such an enzyme monoclonal/antibody conjugate represents a very powerful clinical agent. This approach to cancer therapy, often referred to as "antibody directed enzyme/prodrug therapy" (ADEPT) is disclosed in WO88/07378.
More recently, a similar approach ("VDEPT") has been proposed where in place of an antibody/enzyme conjugate, tumour cells are targeted with a viral vector carrying a gene encoding an enzyme capable of activating a prodrug. The gene may be transcriptionally regulated by tumour specific promoter or enhancer sequences. The viral vector enters tumour cells and expresses the enzyme, in order that a prodrug is converted to an active drug only in the vicinity of the tumour cells (Huber et al, Proc. Natl. Acac. Sci. USA (1991) 88, 8039). Alternatively, non-viral methods for the delivery of genes have been used. Such methods include calcium phosphate co-precipitation, microinjection, liposomes, direct DNA uptake, and receptor-mediated DNA transfer. These are reviewed in Morgan & French Anderson, Annu. Rev. Biochem., 1993,62;191. The term "GDEPT" (gene-directed enzyme prodrug therapy) is used used to include both viral and non-viral delivery systems. The enzyme may be targeted to particular subcellular locations or expressed at the cell surface.
Although the GDEPT and ADEPT systems enhance the concentrations of anti-tumour agents which may be delivered to the site of a tumour, there is still a need to enhance the specificity of drug delivery. In both systems, active drug can be released into the environment of normal cells and cause damage. In the case of ADEPT, this can be caused by activation of prodrug by conjugates which have failed to localise at the tumour site. In GDEPT, transformation of normal tissue may lead to residual levels of expression of the enzyme away from the tumour or active drug may be released from tumour cells. Although ways to increase the specificity of the ADEPT system is disclosed in WO89/10140, there remains a continuing need to improve the level of ADEPT and GDEPT specificity.
Ras is often associated with transformation of cells. Oncogenic ras is over-expressed in a number of human tumours eg. over 50% of colon carcinoma and 90% of pancreatic carcinomas (Marsters et al, 1993, Science 260 1937-1942) also in lung tumours.
It has been shown that inhibition of oncogenic ras in cell culture leads to reversal of the transformed phenotype. Therefore the ability to develop specific inhibitors of ras may have great therapeutic application.
However, one potential pitfall with targeting ras, is the presence of normal non-mutated ras in all normal cells. In normal cells the role of ras is crucial. It is therefore essential to inhibit selectively only activated ras in transformed cells.
Recently, inhibitors of ras farnesyltransferase, which selectively inhibit farnesylation of oncogenic ras, have been described. (Kohl, Science, 260, 1934, 1993; James, ibid, 1937).
SUMMARY OF THE INVENTION
The present invention addresses such problems by the use of a novel class of prodrugs, which are prodrugs of ras inhibitors such as inhibitors of farnesyltransferase. This enzyme is essential for farnesylation of ras which is an absolute requirement for the transforming function of oncogenic ras (Gibbs, 1992, seminars in Cancer biol. 3, 383). The use of ras inhibitors such as farnesyltransfera
REFERENCES:
Kohl et al. Science., vol. 260, No. 5116, pp. 1934-1937, Jun. 25, 1993.
Getz et al. J. Org. Chem. 1992, 57, 1702-1706.
Marais Richard
Springer Caroline Joy
Berch Mark L.
Cancer Research Campaign - Technology Limited
Kifle Bruck
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