University of Texas System

Research, Incorporated

Research Corporation Technologies, Inc.

Abdul R Khokhar

Roman Perez-Soler

Gabriel Lopez-Berestein

Robert A Newman

Zahid H Siddik

Miles P Hacker

John J McCormack

Irwin H Krakoff

David B Brown, Deceased

Michael G Rosenblum

Peter J Kelleher

James L Murray

Salaam Al-Baker

Insook Han

The present invention concerns the use of methods and compositions for the treatment of cancer and other hyperproliferative diseases. In certain embodiments, methods are described for the treatment of cancer and/or hyperproliferative diseases by administration of compositions containing at least one platinum complex alone or in combination with a modulator of glutathione. In particular, the methods may be used to treat cisplatin or carboplatin resistant tumor cells.

Platinum complexes as antitumor agents in combination with biochemical modulation

Antitumor compositions are disclosed, as well as methods of preparing the compositions and methods of using them to inhibit tumor growth in mammals. The invention can take advantage of intraliposomal conversion of a platinum complex having the formula

Delivery and activation through liposome incorporation of diaminocyclohexane platinum(II) complexes

Antitumor compositions are disclosed, as well as methods of preparing the compositions and methods of using them to inhibit tumor growth in mammals. The invention can take advantage of intraliposomal conversion of a platinum complex having the formula ##STR1## where R.sub.1 is diaminocycloalkyl, and R.sub.2 and R.sub.3 each have the formula ##STR2## where R.sub.4, R.sub.5, and R.sub.6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms,

Delivery and activation through liposome incorporation of

Novel 1,4 and 1,2-diaminocyclohexane platinum IV complexes have been synthesized that show activity in vivo against tumor models resistant to cis-platin and tetraplatin. The novel complexes include the chloro, acetate, trifluoroacetate, propionate, butyrate, pentanoate, hexanoate and heptanoate as leaving ligands and 1,4 or 1,2-DACH-amine ligands. The complexes showed good in vitro cytotoxic activity against murine leukemia L1210/0, L1210/DDP and L1210/DACH. High in vivo activity was shown against L1210 leukemia cells and against cis-platin resistant L1210/DDP. Excellent antitumor activity against M5076 was also exhibited by the new complexes. Additionally, the platinum complexes did not elicit any indication of nephrotoxicity in the in vivo tests.

Diamine platinum complexes as antitumor agents

Lipophilic complexes having the structure

Stable liposomal formulations of lipophilic platinum compounds

Water-soluble complexes having the formula: ##STR1## and stereoisomers thereof, where Z.sup.1 and Z.sup.2 are halogens, and X.sup.1 and X.sup.2 are selected from the group consisting of sulfate, phosphate, nitrate, and monocarboxylate, or are jointly dicarboxylate, have been found to have desirable antitumor activity, as well as relatively low levels of toxicity.

Water soluble 1,2-diaminocyclohexane platinum (IV) complexes as

Platinum(IV) complexes with mixed carboxylato ligands having the formula: ##STR1## where X.sup.1 and X.sup.2 are carboxylato, or are jointly dicarboxylato, where .sup.1 Y and Y.sup.2 are carboxylato, and where Z is either diaminocyclohexane or ethylenediamine, have been found to have desirable antitumor activity, as well as relatively low levels of toxicity.

Diamine platinum(IV) complexes having mixed carboxylate ligands as

The present invention involves the synthesis and use of new platinum compounds. These new platinum compounds are easy to encapsulate in liposomes at high efficiencies. They are further characterized as platinum (II) four coordinate complex having the formula: ##STR1## wherein R.sub.1 and R.sub.2 are carboxylato monoanions bearing a hydrophobic radical function or a single carboxylato dianion bearing a hydrophobic radical function and R.sub.3 is a vicinal diaminoalkane or vicinal diaminocycloalkane. The complex is substantially soluble in methanol or chloroform and substantially insoluble in water. Said complex may be incorporated into phospholipid liposomes. Such platinum complexes encapsulated in phospholipid liposomes are useful for chemotherapy of platinum complex-sensitive tumors.

Hydrophobic cis-platinum complexes efficiently incorporated into

The invention relates to a process for the treatment of tumors in animals with water soluble square-planar cis platinum(II) four-coordinate complexes comprising different nonovalent and divalent organic cations. Monovalent cations include galacturonato and N,N-dimethylglycinato and divalent cations include citraconato, 1,1-cyclobutanedicarboxylato, 1,1-cyclopropanedicarboxylato and Z-iminodiacetato where Z is bound to the nitrogen and is ethyl, propyl, isopropyl, n-butyl, secbutyl, ter-butyl, n-amyl, isoamyl or --OH. The treatment of animals comprises administering to the animals a pharmaceutical composition comprising a platinum complex of the composition described.

1,2-diaminocyclohexane-platinum complexes with antitumor activity

The present invention concerns a platinum (II) four-coordinant complex having the formula: ##STR1## wherein R.sub.1 is an alkyl diamine or cycloalkyl diamine and R.sub.2 and R.sub.3 are an alkylcarboxylato containing from five to ten carbon atoms. The R.sub.1 is preferably trans-D,L-1,2-diaminocyclohexane, trans-R,R-1,2-diaminocyclohexane, trans-S,S-1,2-diaminocyclohexane, cis-1,2-diaminocyclohexane ethylene diamine or 1,1-bis(aminomethyl)cyclohexane. The R.sub.2 and R.sub.3 are preferably neohexanoato, neoheptanoato, neononanoato, neodecanoato, neooctanoato, neopentanoato, 2-ethylhexanoato, 2-ehtylbutyrato, 2-propylpropanoato, 2-methyl-2-ethylheptanoato, 2,2-diethylhexanoato, 2,2-dimethyl-4-ethylhexanoato, 2,2-diethyl-4-methylpentanoato, 2,2-dimethyloctanoato, 2-methyl-2-ethylheptanoato, 2,2-diethylhexanoato, 2,2-diethyl-4-methylpentanoato or 2,2,4,4-tetramethylpentanoato. In an important further aspect, the present invention involves preparation and therapeutic use of a liposome comprising a phospholipid and a four-coordinate platinum complex having the formula: ##STR2## wherein R.sub.1 is an alkyl diamine or cycloalkyl diamine and R.sub.2 and R.sub.3 are an alkylcarboxylato containing from about five to about fourteen carbon atoms. The R.sub.1, R.sub.2 and R.sub.3 functions are preferably as described above with the exception that R.sub.2 and R.sub.3 may have even longer alkyl chains such as myristate and laurate, i.e., up to fourteen carbon atoms. For therapeutic use, a pharmaceutical composition comprising this liposome and a pharmaceutically acceptable carrier or diluent may be readily prepared by methods well known to those skilled in the art. The liposomes are useful vehicles for solubilizing the otherwise aqueously insoluble complexes of the present invention. The phospholipids of the liposomes may be one or more of phosphatidylglycerol, phosphatidylcholine, sphingomyelin, phosphatidic acid or phosphatidylserine. The liposomes more preferably consist essentially of phosphatidylglycerol, phosphatidylcholine or a combination thereof and may also comprise cholesterol. The liposomes of the present most preferably comprise phospholipid consisting essentially of dimyristoylphosphatidylglycerol, dimyristoylphosphatidylcholine or a combination thereof.

The present invention relates to monoclonal antibodies specifically binding platinum (II) complex. The monoclonal antibodies of the present invention are characteristically produced by antibody-producing cell lines such as hybridomas. These cell lines may result, for example, from fusion of a neoplastic cell with an antibody-producing animal cell obtained from an animal immunized against a platinum (II) complex. The cellular fusion products include cell lines forming monoclonal antibody specifically binding platinum (II) complex in competition with an antibody produced by: hybridoma strain 1C.sub.1 H.sub.2 A.sub.5, deposited with the American Type Culture Collection, Rockville, MD on May 1, 1987 and having ATCC accession number HB 9411; strain 3A.sub.2 A.sub.1 ; strain 1A.sub.6 A.sub.2 ; strain 3A.sub.6 B.sub.1 or strain 1B.sub.1. The cell lines of the present invention are preferably continuous murine hybridoma cell lines which secrete recoverable quantities of monoclonal antibody, particularly a monoclonal antibody which is of an IgG or IgM isotype.

Monoclonal antibodies binding platinum complexes

Water-soluble complexes having the formula: ##STR1## and stereoisomers thereof, where Z.sup.1 and Z.sup.2 are halogens and X is selected from the group consisting of sulfate, phosphate, nitrate, monocarboxylate, and dicarboxylate, have been found to have desirable antitumor activity, as well as relatively low levels of toxicity.

Growing community of inventors

Houston, TX, United States of America

Abdul R Khokhar