Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1999-05-10
2000-03-14
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514126, 514492, 514553, A61K 3166, A61K 3128, A61K 31185
Patent
active
060373369
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to reducing the toxicity of carboplatin (cis-diammine-1,1-cyclobutanedicarboxylato-platinum II, CBDCA, JM-8 and NSC 241240), using a dithioether as a protective agent.
BACKGROUND OF THE INVENTION
Carboplatin (hereinafter also referred to as "CBDCA" or CBP") is a widely used anticancer drug which is normally used in combination with other anticancer drugs in the treatment of cancers of the lung, head and neck, ovary, esophagus, bladder, testis, and others. One of the most important and common dose limiting toxicities of carboplatin is hematological toxicity. In particular, myelosuppression (depression of blood elements formed within bone marrow) is often manifested in the form of thrombocytopenia, neutropenia, leukopenia, and various forms of anemia. The other major carboplatin-induced toxicity is gastro-intestinal (causing nausea and vomiting).
In order for carboplatin to react with certain nucleic acid sequences in cellular DNA, it must first undergo chemical conversion to an active species by the partial or complete displacement of the cyclobutanedicarboxylato (CBDC) ligands, respectively, by chloride. The chloro and dichloro species are believed to act against cancer cells by reacting with the imidazole nitrogens on DNA. These chloro species are believed to be metabolised in vivo to active hydroxy species.
Carboplatin, unlike cisplatin, is relatively stable in the body. Its cyclobutanedicarboxylato (CBDC) group makes it much less susceptible to displacement by incoming nucleophiles. It is less active than cisplatin towards DNA. Indeed, it is generally given in combination with other anti-cancer drugs. Although less prone to cause the nephrotoxicity associated with cisplatin, it is highly myelotoxic and has gastrointestinal toxicity. It might at first be thought that carboplatin, with its active chloro species, should behave similarly to cisplatin and therefore be further metabolised in the same way. However, this is not so: the body cells most adversely affected by carboplatin-induced toxicity (bone marrow and GI tract cells) are different from those most adversely affected by cisplatin (kidney cells). Thus, the metabolic species responsible for the toxicity cannot be the same. Finding a protective agent for carboplatin therefore represents a new and separate problem from that presented by cisplatin.
SUMMARY OF THE INVENTION
It has now been found that a dithioether having the formula R.sub.1 --(CH.sub.2).sub.n --S--S--(CH.sub.2).sub.m --R.sub.2 (I) wherein: ; and acceptable salt thereof, is a suitable protective agent for carboplatin.
This invention can be represented in different ways according to local patent law. Thus, it includes the use of the dithioether in the manufacture of a medicament for administration in combination with carboplatin to a patient, at substantially the same time or sequentially, whereby the dithioether and the carboplatin become co-present in the blood of the patient and the dithioether serves to reduce the toxicity of the carboplatin. It further includes a method of treating a patient suffering from a cancer susceptible to carboplatin therapy, which comprises administering the dithioether to the patient at the above-recited time. Also within the invention is a medicament for treating cancer in combination with carboplatin therapy, comprising the dithioether.
The preferred dithioether is sodium 2,2'-dithiobis(ethanesulfonate), herein abbreviated to dimesna.
The invention is useful in relation to any cancer treatable by a therapy consisting of or including administration of carboplatin, especially the cancers specifically listed above.
The invention also includes a composition suitable for administration to patients with cancer, comprising carboplatin and a dithioether as defined above, especially in the form of a sterile injectable solution, preferably of pH 2 to 6.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The carboplatin formulation used in the invention will typically be a solution. It can take any form appropriate to o
REFERENCES:
patent: 5789000 (1998-08-01), Hausheer et al.
Haridas Kochat
Hausheer Frederick H.
Murali Dhanabalan
Peddaiahgari Seetharamulu
Reddy Dasharatha G.
BioNumerik Pharmaceuticals, Inc.
Dodd Thomas J.
Goldberg Jerome D.
LandOfFree
Reducing toxic effects of carboplatin using dithioethers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Reducing toxic effects of carboplatin using dithioethers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Reducing toxic effects of carboplatin using dithioethers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-169354