Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1992-11-25
1995-09-05
Scheiner, Toni R.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 723, 435 72, 435 79, 435 792, 435975, 436 63, 436 64, 436813, 436516, G01N 33574, G01N 3353, C12Q 168
Patent
active
054478430
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a method of predicting disease-free survival in cancer patients based on overproduction levels of one or more stress response proteins from primary tumors. The method is particularly useful in predicting tumor recurrence in node-negative breast cancers.
Stress response proteins, srp's, have been recognized for several years, although in earlier terminology they were commonly called heat shock proteins, hsp's, because they were originally discovered as families of related proteins rapidly overproduced in divergent species in response to temperature stress. Subsequently these proteins were found to be induced in response to a variety of environmental stresses, including stimuli such as heat, heavy metals, toxins, drugs, hypoxia, and alcohol.
The precise function of stress response proteins is still largely a matter of speculation. It is widely assumed that these proteins protect cells from the effects of stress, but little is known about the mechanisms of induction and even less is understood about the relationships between number and amount of protein induced and the underlying physiological phenomenon.
There have been speculations that pretumorous or tumor cells might express increased amounts of stress response proteins, leading some workers to search for a relation between levels of these proteins and tumor manifestation. But although readily induced, the higher levels of heat stress proteins did not appear to relate to increased probability of tumor recurrence; in fact, some studies indicated that metastatic tumor burden generally decreased following induction of stress proteins (S. P. Tomasovic and D. R. Welch, Hyperthermia 2, 253 (1986)). Subsequent work by McGuire and colleagues, however, demonstrated that an estrogen-induced protein found in MCF-7 human breast cancer cells was identical to one of the earlier discovered heat shock proteins, hsp27, and that hsp27 might be associated with node-negative breast cancer patients at high risk of recurrence. Nevertheless, correlation factors were relatively weak and not sufficient to suggest a clinically useful method of prognostication.
The phenomenon of heat shock response was first observed nearly three decades ago by Ritossa (F. Ritossa, Experientia 18, 571 (1962)) who found that an increase in temperature from 20.degree. to 37.degree. C. as well as exposure to certain chemicals such as dinitrophenol or sodium salicylate, leads to a remarkable change in the puffing pattern of polytene chromosomes in salivary glands of fruit flies (Drosophila busckii). Nearly 12 years after this observation, Tissieres et al. (A. Tissieres, H. K. Mitchell, U. M. Tracy, J. Mol. Biol. 84, 389 (1974)) reported the induction of a set of proteins called heat shock proteins (hsp's), as a consequence of heat shock. Today, practically all types of organisms are known to respond to an increase in temperature in a basically similar fashion by massive synthesis and accumulation of a group of hsp's with almost no tissue or cell type specificity. Major hsp's are now known to be very highly conserved through evolution, strongly suggesting their vital role in survival of the organisms. Nearly all species induce the synthesis of proteins in the size ranges of 80 to 90 kDa, 68 to 74 kDa, and 18 to 30 kDa. In the past few years, the genes encoding the hsp's have been isolated and through sequence analysis have been placed into three "universal" families. These are known by their molecular weights: hsp90, hsp70, and hsp27 (the exact molecular weight differs slightly from organism to organism). These hsp genes contain a conserved sequence of 14 base pairs in the 5' noncoding region, the Pelham box, which serves as the promoter for hsp mRNA transcription. Recently, a relationship between the sequences of hsp's and another family of stress proteins, the glucose-regulated proteins (grp's), has been reported. These proteins are oversynthesized in response to glucose starvation. Two major grp's have been identified as grp94 and grp78.
Although the precise function of stres
REFERENCES:
patent: 5188964 (1993-02-01), McGuire et al.
Chamness Gary C.
Clark Gary M.
Fuqua Suzanne A.
McGuire, deceased William L.
Tandon Atul K.
Board of Regents , The University of Texas System
Scheiner Toni R.
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