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Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes

a technology of alternative alleles and products, applied in the field of proliferative disorders, can solve the problems of high risk of toxic side effects to patients, high risk of adverse drug events, and damage to vital organs, and achieve the effects of reducing the activity of a cellular component, reducing the rate of a cellular process, and reducing the level of a cellular constituen

Inactive Publication Date: 2002-09-12
VARIAGENICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] Thus, the present invention is directed to the use of genes which are referred to as conditionally essential genes as targets or as indicators of an appropriate antiproliferative treatment. Such conditionally essential genes are those which are necessary or beneficial to the growth, proliferation, or survival of a cell under particular environmental conditions, but not under normal in vivo conditions. Treatment methods involving such genes can provide enhanced sensitivity of cancer cells to a variety of different anti-proliferative treatments, including radiation and administration of various compounds. Unless otherwise indicated, the term "essential" includes both strictly essential and beneficial to cell growth or survival.
[0055] A "therapeutic effect" results, to some extent, in a measureable response in the treated disease or condition. Thus, a therapeutic effect can include a cure, or a lessening of the growth rate or size of a lesion such as a tumor, or an increase in the survival time of treated patients compared to controls, among other possible effects.

Problems solved by technology

Although many anticancer drugs have been and continue to be discovered, there remains the immense problem of developing drugs that will be specifically toxic to cancer cells without killing normal cells and causing toxic, often permanent, damage to vital organs or even death.
With some cancer therapeutics this ratio is in the range of 2-4, indicating a high risk of toxic side effects to the patient.
Indeed, most anticancer drugs are associated with a high incidence of adverse drug events.
The poor therapeutic index of most anticancer drugs not only limit the clinical efficacy of these drugs for the treatment of cancer, but limits their usefulness for treating many non-malignant, proliferative disorders.

Method used

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  • Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
  • Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
  • Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes

Examples

Experimental program
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third embodiment

[0172] In one embodiment, the DNA sequence of the desired allelic form of the target gene can be cloned by insertion into an appropriate expression vector and translated into protein in a prokaryotic or eukaryotic host cell. The protein can be recovered and used as an antigen to elicit the production of specific antibodies. In another embodiment, the DNA of the desired allelic form of the target gene is amplified by PCR technology and is subsequently translated in vitro into protein to be used as the antigen to elicit the production of specific antibodies. A third embodiment is to use the DNA sequence of the alternative alleles as a basis for the generation of synthetic peptides representing the amino acid sequence of the alleles for use as antigen to elicit the production of specific antibodies.

[0173] Antibodies can be generated either by standard monoclonal antibody techniques or generated through recombinant based expression systems. See generally, Abbas, Lichtman, and Pober, Cel...

example 1

Dihydropyrimidine Dehydrogenase (DPD)

[0223] DPD is conditionally essential

[0224] Dihydropyrimidine Dehydrogenase is essential for cell survival in the presence of pyrimidine nucleotide analogs such as 5-FU and fluorodeoxyaridine. 5-fluorouracil (5-FU) and related compounds are antineoplastic drugs used in the treatment of breast, gastrointestinal, head and neck and other cancers. These drugs have widely varying clinical effects in cancer patients, ranging from induction of complete response (tumor disappearance) in some patients to severe toxicity in others. There is currently no reliable basis for predicting individual patient responses, and therefore patients receiving 5-FU must be monitored carefully for toxic reactions.

[0225] There are a variety of anabolic and catabolic pathways that affect the action of 5-FU (reviewed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th edition). For example, in order to exert its antiproliferative effects the pyrimidine analo...

example 2

Fanconi Anemia genes A, B, C, D, E, F, G and H (FAA, FAB, FAC, FAD, FAE, FAF, FAG, FAH)

[0235] The Fanconi Anemia genes are conditionally essential.

[0236] The Fanconi Anemia genes are essential for cell growth or survival in the presence of DNA cross linking agents. In order for cells to survive or proliferate in an abnormal environment characterized by the presence of DNA cross linking molecules such as Mitomycin C and diepoxybutane it is necessary that the cells are capable of efficiently repairing damage caused by these agents. Cells contain proteins necessary for such repair. One way such repair proteins can be identified is by absence of function in specific patients who, as a consequence, are particularly susceptible to the toxic effects of cross linking agents.

[0237] Fanconi Anemia (FA) is a hereditary disease, autosomal recessive in transmission, characterized by progressive bone marrow failure, birth defects and predisposition to malignancies. FA patients are hypersensitive ...

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Abstract

Disclosed are methods for the treatment of proliferative disorders using compounds and / or environmental conditions which result in a difference in sensitivity of targeted and non-targeted cells. Certain of the methods involve the identification and use of allele-specific inhibitors of conditionally essential genes.

Description

BACKGROUND[0001] This invention is concerned with the field of treatment of proliferative disorders, including malignant and nonmalignant proliferative diseases.[0002] The following information is provided to assist the understanding of the reader, none of that information is admitted to be prior art to the present invention.[0003] The treatment of cancer is one of the most heavily investigated areas in biomedical research today. Although many anticancer drugs have been and continue to be discovered, there remains the immense problem of developing drugs that will be specifically toxic to cancer cells without killing normal cells and causing toxic, often permanent, damage to vital organs or even death. One common measure of the clinical usefulness of any anticancer drugs is its therapeutic index: the ratio of the median lethal dose (LD.sub.50) to the median effective dose (ED.sub.50) of the drug. With some cancer therapeutics this ratio is in the range of 2-4, indicating a high risk ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K41/00C12Q1/68C12Q1/6886
CPCA61K41/00C12Q1/6886C12Q2600/136
Inventor HOUSMAN, DAVID E.LEDLEY, FRED D.STANTON, VINCENT P. JR.
Owner VARIAGENICS
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