Methods to Treat Cancer with 10-propargyl-10-deazaaminopterin and Methods for Assessing Cancer for Increased Sensitivity to 10-propargyl-10-deazaaminopterin

a technology of 10-propargyl and 10-deazaaminopterin, which is applied in the field of methods to treat cancer with 10-propargyl10deazaaminopterin, can solve the problem that the highest dose used was in fact toxic to mi

Inactive Publication Date: 2008-08-07
SLOAN KETTERING INST FOR CANCER RES
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These data were equivocal because of the small number of mice used in the test (3 per dosage), the absence of any standard deviation information which would quantify the reliability of the data, and the fact that the highest dose used was in fact toxic to the mice.

Method used

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  • Methods to Treat Cancer with 10-propargyl-10-deazaaminopterin and Methods for Assessing Cancer for Increased Sensitivity to 10-propargyl-10-deazaaminopterin
  • Methods to Treat Cancer with 10-propargyl-10-deazaaminopterin and Methods for Assessing Cancer for Increased Sensitivity to 10-propargyl-10-deazaaminopterin
  • Methods to Treat Cancer with 10-propargyl-10-deazaaminopterin and Methods for Assessing Cancer for Increased Sensitivity to 10-propargyl-10-deazaaminopterin

Examples

Experimental program
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example 1

[0076]FIG. 4 shows a synthetic scheme useful in preparing 10-propargyl-10-dAM in accordance with the invention. A mixture of 60% NAH in oil dispersion (1.06 g, 26.5 mmol) in 18 mL of sieve-dried THF was cooled to 0° C. The cold mixture was treated with a solution of homoterephthalic acid dimethyl ester (5.0 g, 24 mmol. compound 1 in FIG. 4) in dry THF (7 mL), and the mixture was stirred for 1 hour at 0° C. Propargyl bromide (26.4 mmol) was added, and the mixture was stirred at 0° C. for an additional 1 hour, and then at room temperature for 16 hours. The resulting mixture was treated with 2.4 mL of 50% acetic acid and then poured into 240 mL of water. The mixture was extracted with ether (2.times.150 mL). The ether extracts were combined, dried over Na2SO4, and concentrated to an orange-yellow oil. Chromatography on silica gel (600 mL of 230-400 mesh) with elution by cyclohexane-EtOAc (8:1) gave the product α-propargylhomoterephthalic acid dimethyl ester (compound 2) as a white soli...

example 2

[0083]This example describes testing of 10-propargyl-10-dAM and MTX for cytotoxicity against human lymphoma cell lines.

[0084]10-propargyl-10-dAM preparation prepared in accordance with Example 1 and an MTX preparation were tested for cytotoxicity against a panel of five human lymphoma cell lines. Experiments were performed as described previously. (Sirotnak et al., Cancer Chemother. Pharmacol. 12: 18-25 (1984). In brief, 2.5 to 5×103 cells were plated per well in 96-well flat bottom plates. Drug was added in a 0.9% NaCl solution (pH 7.0) over a range of concentrations, and cells were continuously exposed to drug for 5 days. Colorimetric dye (XTT or Alamar blue) was added for an addition period of time (XTT dye, 6 hours, Alamar blue, 24 hours). Each plate was then read on an automated plate reader at 590 nm. The percentage of inhibition was calculated as growth of cells exposed to drug divided by growth of controls (cells incubated with media only). IC50 values were determined as the...

example 3

[0085]This example describes the effects of 10-propargyl-10-dAM used in a Phase I / II study on T-cell lymphomas.

[0086]In this study, patients with aggressive lymphoma were enrolled, including three patients with drug-resistant T-cell lymphoma. The following case summaries have been obtained. Each of these patients was also treated with folic acid (1 mg / m2 daily starting 1 week prior to treatment with 10-propargyl-10-dAM) and Vitamin B12 (1 mg / mg / m2 monthly) supplementation.

[0087]Patient 1 had a diagnosis of Peripheral T-cell Lymphoma, Stage 1V. Demographics: 48 Year old male; Prior Treatment: CHOP.times.4 cycles (July 2002-November 2002) refractory, ICE.times.2 cycles (December 2002) refractory, Campath (March 2003-June 2003)—mixed response; Pre-Treatment Staging: Extensive disease cutaneous disease. Treatment on Study: 10-propargyl-10-dAM 135 mg / m2 times.1 dose. Toxicitics observed were Grade 3 stomatitis; neutropenia grade 3; sepsis; Response: Essentially complete remission by PET ...

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Abstract

The present invention relates to a method for assessing the sensitivity of a patient's cancer to treatment with 10-propargyl-10-deazaaminopterin and a method for selecting a patient for treatment of cancer with 10-propargyl-10-deazaaminopterin, by determining the amount of a selected polypeptide expressed by the cancer and comparing the amount with the amount of the selected polypeptide expressed by a reference cancer, wherein the polypeptide includes a member of folate pathways within cells and may include at least one of reduced folate carrier-1 enzyme (RFC-1), dihydrofolate reductase (DHFR), folylpoly-gamma-glutamate synthetase (FPGS), thymidylate synthase (TS), γ-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT). The present invention also relates to the use of 10-propargyl-10-deazaaminopterin in the treatment of multiple myeloma.

Description

STATEMENT OF RELATED APPLICATIONS[0001]The present application claims the benefit of U.S. Provisional Application No. 60 / 869,528, filed Dec. 11, 2006, which application is incorporated herein by reference in its entirety. The present invention claims priority from and is a continuation in part application of pending U.S. Ser. No. 11 / 568,254, filed Oct. 24, 2006, which is a 371 of PCT / US2005 / 019170 filed on May 31, 2005, claiming priority to U.S. Ser. No. 60 / 521,593, filed on May 30, 2004; each of which are incorporated by reference herein in their entireties.TECHNICAL FIELD[0002]The present invention relates to methods to treat cancer with 10-propargyl-10-deazaaminopterin and methods for assessing cancers and selecting patients for treatment based for increased sensitivity to 10-propargyl-10-deazaaminopterin.BACKGROUND OF THE INVENTION[0003]10-Propargyl-10-deazaaminopterin (herein “PDX” or “10-propargyl-10dAM” or “pralatrexate”) is a member of a large class of compounds which have b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4985C12Q1/00A61P35/00
CPCG01N2800/52G01N33/5023A61P35/00
Inventor O'CONNOR, OWEN A.SIROTNAK, FRANCIS
Owner SLOAN KETTERING INST FOR CANCER RES
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