Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Patent
1994-07-08
1997-08-19
Feisee, Lila
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
4241361, 4241551, 4241831, 424809, 424 941, 436819, 514 2, 530350, 5303873, 5303877, 5303897, 5303917, A61K 39395, A61K 3843, C07K 1628, C07K 1700
Patent
active
056585683
DESCRIPTION:
BRIEF SUMMARY
This invention relates to potentially cytotoxic agents which may be targeted to selected cells, and is particularly concerned with the action of agents used in the treatment of cancer.
Most forms of cancer tend to disseminate in the body at an early stage and the ultimate aim of cancer therapy is to achieve elimination of cancers, preferably without incurring serious toxic effects on host systems. Combinations of cytotoxic agents have proved curative in a small range of relatively uncommon cancers, but single agents and combinations of them have failed to achieve major therapeutic benefits in most patients with the common cancers of lung, breast, colon, rectum, pancreas, prostate etc.
Cytotoxic agents can only be given by intermittent dose schedules because of their effects on normal tissues in which cell renewal is active such as haemopoietic tissues and epithelia of the alimentary tract. The rest period between treatments which is necessary to allow recovery of these normal tissues from the effects of the cytotoxic substances tends to be of much greater duration than the period of administration of the cytotoxic agents.
Substances involved in cell division are the commonest targets for cytotoxic agents and amongst these are substances involved in the synthesis of nucleotides, the basic components of DNA and RNA. The enzymes ribonucleotide reductase, dihydrofolate reductase and thymidine synthetase are typical targets. The enzyme dihydrofolate reductase acts on a dietary factor, folic acid, to produce the active co-enzyme 5,10-methenyltetrahydrofolate. The co-enzyme is required for one carbon transfer in various syntheses including that of pyrimidines required for DNA synthesis. The widely used drug methotrexate (2,4-diamino-N.sup.10 -methylpteroylglutamic acid) acts by binding strongly to dihydrofolate reductase preventing regeneration of active tetrahydrofolate and thus interrupting DNA synthesis and leading to death of cells entering S phase of the cell cycle in which DNA is duplicated. Methotrexate is generally available, for example from Cyanamid Inc.
The drug trimetrexate (NSC 352122; 2,4-diamino-5-methyl-6-[3,4,5-trimethoxyanilino methyl]quinazoline) also acts by binding to dihydrofolate reductase but whereas methotrexate enters cells via the folate receptors, trimetrexate enters by alternative mechanism(s). The synthesis of trimetrexate is disclosed by Baker (1967) in Design of site-directed irreversible enzyme inhibitors, Wiley, New York, and by Elslager et al (1974) Lectures in heterocyclic chemistry, Vol. 2, pp 97/5-133 (Castle & Townsend, ed), Hetero Corp, Oren, Utah. Trimetrexate is generally available from US Biosciences, One Tower Bridge, 100 Front Street, Suite 400, West Conshohocken, Pa. 19428, USA.
Methotrexate resembles natural folates in having a terminal glutamic acid moiety which can be cleaved by carboxypeptidase G2, whereas trimetrexate is not susceptible to the action of this enzyme (Bagshawe (1985) Clinical Radiol. 36, 545-551 ). We have previously reported that the action of trimetrexate on colonic cancer cells in vitro can be enhanced by the addition to the culture medium of a folate degrading enzyme carboxypeptidase G2 (Searle et al (1990) Biochemical Pharmacol. 39, 1787-1791. We have also shown that this enzyme retains activity when conjugated to antibodies or antibody fragments (Searle et al (1988) Bact. J. Cancer 53, 377-384).
The biological effect of both methotrexate and trimetrexate can be reversed by administering an end product of the reaction they block, or by a more readily available analogue known as folinic acid [5-formyl tetrahydrofolic acid]. Folinic acid is widely available, for example as Leucovorin from Cyanamid Inc, but also from Wellcome Inc, and Farmitalia. If folinic acid is given in sufficient dosage concurrently with methotrexate or trimetrexate their actions are blocked. It has been found useful in the treatment of some cancers to use folinic acid in conjunction with methotrexate in carefully timed and dose controlled sequences. The methotrexate-folinic
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Feisee Lila
Lucas John
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