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- Bookedited by Monica Mita, Alain Mita, Eric K. Rowinsky.Summary: This book describes the challenges involved in developing mTOR inhibitors for cancer treatment, starting with an in-depth examination of their molecular mechanism of action, with emphasis on the class side-effects, efficacy and mechanisms of resistance, as well as on promising novel directions for their development, including novel compounds and rational combinations with other anti-neoplastic drugs. Over the last 10 years, inhibitors of mTOR have emerged as a major class of anticancer drugs. Two rapamycin analogs are currently approved for the treatment of renal cell carcinoma, and it is estimated that a variety of other tumor types could benefit from mTOR inhibition, with numerous clinical trials (including pivotal registration trials) already underway. Second-generation small-molecule inhibitors of the pathway have also shown promise in terms of their superior tolerability and efficacy and are undergoing extensive clinical evaluation, with an estimated 30+ compounds currently under evaluation.
Contents:
Forward
Past
mTOR inhibitors: a little bit of history
Present
The mTOR pathway
The evolving role of mTOR inhibitors in renal cell carcinoma
The role of mTOR inhibitors in breast cancer
The role of mTOR inhibitors in neuroendocrine tumors
New indications of mTOR inhibitors in rare tumors
The role of mTOR inhibitors in the treatment of hematological malignancies
The clinical pharmacology and toxicity profile of rapalogs
Resistance to mTOR inhibitors
Rational combinations of mTOR inhibitors as anticancer strategies
Future
Predictive biomarkers of response to mTOR inhibitors
The potential future indication of rapamycin analogs for the treatment of other solid tumors
mTOR inhibition beyond rapalogs
mTOR, aging and cancer: the missing link?
New study design for mTOR inhibitors and other biological agents
Future directions for the development of mTOR inhibitors. - ArticleEichler DC, Lehman IR.J Biol Chem. 1977 Jan 25;252(2):499-503.The deoxyribonuclease specified by the recB and recC genes of Escherichia coli (recBC DNase; exonuclease V) has been purified to near homogeneity by a new procedure. Although hydrolysis of even a single nucleotide from a duplex DNA molecule by the pure enzyme is absolutely dependent upon ATP, the extent of phosphodiester hydrolysis is strongly inhibited by ATP concentrations of 0.2 mm or greater, and the initial rate is unaffected. Under these conditions, the extent of DNA hydrolysis is proportional to enzyme concentration. In contrast, neither the rate nor the extent of hydrolysis of single-stranded DNA nor ATP is affected by high concentrations of ATP. The amount of large single-stranded polynucleotide generated by the action of the recBC DNase increases as the ATP concentration increases and, at 0.5 mM ATP, becomes equivalent to the amount of acid-soluble nucleotide formed. These findings suggest that high intracellular concentrations of ATP affect the mechanism of the recBC DNase so as to limit the extent of hydrolysis of duplex DNA, while at the same time favoring the formation of single-stranded regions within the duplex. Such regions may be essential intermediates in the recombination process.