Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1995-04-04
1997-12-30
Elliott, George C.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
530300, 5303871, 536 231, 536 245, C12Q 168, C07K 200, C07K 1600, C07H 2104
Patent
active
057028907
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This application is directed to therapeutic inhibitors to treat cancer and strategies for the development of cancer treatments having a high therapeutic index.
BACKGROUND OF THE INVENTION
The targeting of chemotherapeutic agents to tumor cells is one of the most heavily investigated areas in biomedical research today. Although effective antineoplastic agents have been and continue to be discovered, there remains the immense problem of targeting these highly toxic agents specifically to tumor cells so that they do not also kill normal somatic cells and thereby cause permanent damage to vital organs or even death. Indeed, one measure of the clinical usefulness of any antineoplastic agent 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 close to one, indicating a high level of toxic side effects to the patient.
SUMMARY OF THE INVENTION
Cancer cells almost invariably undergo a loss of genetic material (DNA) when compared to normal cells. This deletion of genetic material is technically referred to as "loss of heterozygosity" (LOH). Recognizing that almost all, if not all, varieties of cancer undergo LOH, and that these regions are quite extensive, the inventor evaluated the genetic content of deleted regions in cancer cells and realized that genes vital for cell viability or cell growth are frequently deleted. Further investigation has culminated in the discovery that the loss of genetic material from cancer cells sometimes results in the selective loss of one of two alleles of a certain vital gene at a particular locus on the chromosome. Based on this analysis, the inventor has devised a unique therapeutic strategy for the treatment of cancer. This strategy will result in agents characterized by a high therapeutic index. The strategy includes (1) identification of alternative alleles of genes coding for proteins vital for cell viability or growth; (2) identification of the absence of one of these alleles in cancer cells and (3) development of specific inhibitors of the single remaining allele of the vital gene retained by the cancer cell after LOH.
The inhibitors described in this invention are specific for one allele of a gene that codes for a protein vital to cell growth or cell viability. Exposure to the inhibitor inhibits proliferation or kills cancer cells which have undergone genetic deletion such that the cells only express the single allelic form of the vital protein against which the inhibitor is targeted. Normal cells exposed to the inhibitor are spared from the toxic effects of the inhibitor because the remaining activity of the unblocked alternative allele is adequate to permit continued cell viability and growth. This differential effect of the inhibitor on cancer cells and normal cells accounts for the high therapeutic index of the inhibitors of this invention when used as antineoplastic agents. Toxicity of the inhibitor to normal cells is therefore low, compared to most currently available antineoplastic agents.
DETAILED DESCRIPTION OF THE INVENTION
I. Introduction
All genes, except those of the two sex chromosomes, exist in duplicate in human cells, with one copy of each gene (allele) found at the same place (locus) on each of the paired chromosomes. Each chromosome pair thus contains two alleles for any gene--one from each parent. This redundancy of allelic gene pairs on duplicate chromosomes provides a safety system; if a single allele of any gent pair is defective or absent, the surviving allele will continue to produce the coded protein.
Because humans are genetically heterogeneous, technically referred to as DNA polymorphism, many of the paired alleles of genes differ from one another. When the two alleles are identical, the individual is said to be homozygous for that pair of alleles at that particular locus. Alternatively, when the two alleles are different, and usually the differences are small, the individual is heterozygous at
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Elliott George C.
K.O. Technology, Inc.
Schwartzman Robert
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