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Cephalotaxine Alkaloid Compositions and Uses Thereof

Inactive Publication Date: 2011-01-13
CHEMGENEX PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Metal coordination compounds such as cisplatin and carboplatin similarly directly attack the nucleic acid structure resulting in lesions that are difficult for the cells to repair which, in turn, can result in cell death.
Fradulent nucleosides include pyrimidine and purine nucleoside analogs which are inappropriately incorporated into nucleic polymer structures and ultimately cause premature DNA chain termination.
Certain enzymes that affect the integrity and functionality of the genome can also be inhibited in cancer cells by specific chemical agents and result in cancer cell death.

Method used

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  • Cephalotaxine Alkaloid Compositions and Uses Thereof
  • Cephalotaxine Alkaloid Compositions and Uses Thereof
  • Cephalotaxine Alkaloid Compositions and Uses Thereof

Examples

Experimental program
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Effect test

example 1

Chemopotentiation of Cisplatin (CDDP) by Homoharringtonine (HHT)

[0020]Transplantable experimental murine fibrosarcomas (2×105 RIF-1 cells) were grown intradermally in the flanks of 3 month old female C3H mice (Charles River, Holister, Calif.). When the tumors reached a volume of approximately 100 mm3, the mice were randomly assigned to each experimental group (4 mice per group).

[0021]The experimental compositions were prepared as described in Table 2.

TABLE 2AgentDoseSolventSupplierHomoharringtonine2 mg / kgDMSONCICisplatin4 mg / kgWater for injectionDavid Bull Labs

[0022]The chemopotentiator, homoharringtonine, was obtained from NCI and was made to the appropriate concentration in DMSO. Cisplatin (David Bull Laboratories-Mulgrave, Australia, lot. 5201844x) was made to the appropriate concentration in water for injection. The compositions were injected systemically (i.e., intraperitoneally, i.p.), in a volume of 100 microliters. For the treatment of group 3, the chemopotentiator, homoharr...

example 2

Effect of Homoharringtonine, Alone and in Combination with Other Chemotherapeutics on RIF-1 Tumor Growth in C3H Mice

[0026]The RIF-1 murine fibrosarcoma tumor model was used to evaluate the antitumor activity of homoharringtonine, alone and in combination with various antiproliferative agents. The antiproliferative agents used include those that affect nucleic acid (e.g., DNA) integrity (e.g., cisplatin, cytarabine, camptothecin, etoposide, 5-fluorouracil, or amonafide), agents that affect structural proteins (e.g., paclitaxel, vinblastine, or colchicine) or cytoplasmic enzymes (e.g., genistein).

[0027]Homoharringtonine (HHT-NCI) was obtained from NCI as a powder. Homoharringtonine (HHT-Clin) was obtained from Hangzhou Minsheng Pharmaceutical Group (Hangzhou, China), in 1 mL vials, prediluted with water to 1 mg / mL. Cisplatin for Injection, USP, was obtained from David Bull Labs (Mulgrave, Australia), Lot No. 5201844x, as a lypholized powder. Paclitaxel was obtained from Bristol Myers ...

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Abstract

A method of treatment of a host with a cellular proliferative disease, comprising contacting the host with a cephalotaxine and an antiproliferative agent, each in an amount sufficient to modulate said cellular proliferative disease, is described. In some embodiments, the cephalotaxine comprises homoharringtonine (cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methyl pentyl)butanediocate ester). Antiproliferative agents of the invention comprise alkylating agents, intercalating agents, metal coordination complexes, pyrimidine nucleosides, purine nucleosides, inhibitors of nucleic acid associated enzymes and proteins, and agents affecting structural proteins and cytoplasmic enzymes.

Description

[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 189,699, filed Mar. 15, 2000.FIELD OF THE INVENTION[0002]The technical field of the invention is the use of cephalotaxine alkaloids with antiproliferative agents to treat a host with a cellular proliferative disease.BACKGROUND OF THE INVENTION[0003]There is considerable interest in modulating the efficacy of currently used antiproliferative agents to increase the rates and duration of antitumor effects associated with conventional antineoplastic agents.[0004]Conventional antiproliferative agents used in the treatment of cancer are broadly grouped as chemical compounds which (1) affect the integrity of nucleic acid polymers by binding, alkylating, inducing strand breaks, intercalating between base pairs or affecting enzymes which maintain the integrity and function of DNA and RNA; (2) chemical agents that bind to proteins to inhibit enzymatic action (e.g., antimetabolites) or the function of structural p...

Claims

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Application Information

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IPC IPC(8): A61K38/43A61K31/55A61K31/7064A61K31/7076A61K38/00A61K33/24A61P35/00A61K31/352A61K45/00A61K31/36A61K31/473A61K31/4745A61K31/475A61K31/513A61K31/70A61K31/7042A61K31/7048A61K31/7068A61K33/243A61K45/06
CPCA61K31/4745A61K31/475A61K31/513A61K31/55A61K31/70A61K31/7048A61K45/06A61K33/24A61K31/7076A61K2300/00A61P35/00A61K33/243
Inventor BROWN, DENNIS M.
Owner CHEMGENEX PHARMA
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