Drug Innovation & Design, Inc.

General Oncology, Inc.

Other

Arnold Glazier

Ivan Yanachkov

Milka Yanachkova

The present invention relates to methods for the treatment of metastatic cancer. Methods of treating metastatic cancer by administration of a set of drugs overcome multiple mechanisms of melphalan resistance and hypersensitize cancer cells to melphalan are described. The methods involve the administration of drug(s) that induce oxidative stress in cancer cells, in conjunction with melphalan on a defined schedule.

Methods for the effective treatment of metastatic cancer

The present invention relates to methods and sets of drugs for the effective treatment of metastatic cancer and the administration of a set of drugs that overcome mechanisms of resistance to DNA-damaging agents, thereby sensitizing cancer cells to said DNA-damaging agents. The methods involve the administration of a set of drugs comprising melphalan, BCNU, hydroxocobalamin, and ascorbic acid. In a preferred embodiment, ethanol is also added to the set of drugs and bone marrow toxicity is reversed with an infusion of bone marrow stem cells. The methods also involve the depletion of GSH in tumors and the selective delivery of drugs to solid tumors. The methods also involve preventing the loss of catalase function and preventing oxidant-induced hemolysis and/or methemoglobin formation in subjects treated with oxidant drugs or agents that generate hydrogen peroxide, wherein said methods comprise the systemic administration of ethanol.

Combination therapy for metastatic cancer

Disclosed are novel prodrugs represented by the following structural formula;

Acyclovir diester derivatives

Disclosed are novel prodrugs represented by the following structural formula:

Methods of preparing acyclovir prodrugs

The composition and methods of synthesis of phosphorus prodrugs are described. These methods can be used to convert negatively charged phosphorus bearing drugs into neutrally charged; lipid soluble prodrugs which are able to passively diffuse into cells and into tissues in vivo. Prodrugs for a variety of antiviral and anti-leukemic agents are described.

Phosphorous prodrugs

Disclosed are novel prodrugs represented by the following structural formula: ##STR1## Z is oxygen or sulfur; Y is, together with a hydroxy group, acyclovir or an analog of acyclovir; A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester, which can be converted in vivo to a hydroxy or amino group. Also disclosed is a method of treating a viral infection in an individual or animal. The method comprises administering to the individual or animal a therapeutically effective amount of a prodrug represented by structural formula shown above.

Disclosed are novel prodrugs represented by the following structural formulas: ##STR1## Z is oxygen or sulfur; n is 1 or 2; Y is, together with a hydroxy group, acyclovir or an analog of acyclovir; A is a group which can be metabolized in vivo to a give a modified A such that the phosphoester bond (modified A)--O undergoes cleavage in vivo. Also disclosed is a method of treating a viral infection in an individual or animal. The method comprises administering to the individual or animal a therapeutically effective amount of a prodrug represented by structural formula shown above.

Guanine analog phosphates

The composition and methods of synthesis of phosphorus prodrugs are described. These methods can be used to convert negatively charged phosphorous bearing drugs into neutrally charged; lipid soluble prodrugs which are able to passively diffuse into cells and into tissues in vivo. Prodrugs for a variety of antiviral and anti-leukemic agents are described.

Phosphorus prodrugs

The composition, synthesis, and applications of tumor associated protease activated prodrugs of phosphoramide mustard, isophosphoramide mustard and analogs with detoxification functionalities are described. These drugs release a cytotoxic phosphoramide mustard analog following activation by tumor associated proteases and esterases. The general structure for these drugs is: ##STR1## Wherein R1 is a beta-X-ethyl-amino group which may optionally bear substituents on the nitrogen or carbon atoms; wherein X is a good leaving group such as a halogen; R2 is a beta-X-ethyl-amino group which may optionally bear substituents on the nitrogen or carbon atoms; or an amino group (NH.sub.2) which may optionally be substituted. Wherein A is a benzyloxy derivative with one or more acyloxy or acylamino groups in para or ortho portions relative to the phosphoester; and wherein the acyloxy or acylamino groups are not (substituted or unsubstituted) p-guanidino-benzoyloxy groups or p-guanidino-benzoylamino groups.

Tumor protease activated prodrugs of phosphoramide mustard analogs with

Phosphorous prodrugs and therapeutic delivery systems using same

The composition, methods of synthesis, and applications of a new class of tumor selective antineoplastic drugs is described. These novel antineoplastic agents are of the general structure: A-C-B. The agents are designed with two key functionalities: a trigger which toxifies the drug; (A) and a deactivator which detoxifies the drug (B) The trigger is selected such that it is activated by an enzyme which is present in elevated levels in the tumor. The deactivator is selected such that it is actuated by an enzyme ubiquitous to all tissues. The fate of the drug in a given cell is then determined by the ratio of the enzymatic activity that triggers toxication to the enzymatic activity which detoxifies the drug. The partitioning of the drug between toxic metabolite and nontoxic metabolite defines the resulting specificity of cytotoxic effect. The application of this invention is exemplified by a new class of antineoplastic drugs which are designed to be selectively toxic for tumor cells bearing the enzyme guanidinobenzoatase.

Growing community of inventors

Newton, MA, United States of America

Arnold Glazier