One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype

The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

http://science.sciencemag.org/content/sci/321/5897/1807.full.pdf

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

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IDH1 and IDH2 Mutations in Gliomas

p53, guardian of the genome

A method is provided for treating a patient afflicted with a hematologic disorder such as chronic leukemia and the myelodysplastic syndromes. The method includes administering to the patient an effective amount of a water-insoluble 20(S)-camptothecin compound with a closed lactone ring, a derivative thereof, or a mixture thereof. In a preferred method, the compound administered is 9-nitro-20(S)-camptothecin. The compound can be administered orally, intramuscularly, transdermally, subcutaneously, or parenterally.

Method for treating hematologic disorders with water insoluble 20 (S)-camptothecin

The cytotoxicity of 5-hydroxyuridine (OHUrd), 5-FU, and 5-fluorodeoxyuridine was determined by colony assays for three human colon adenocarcinoma cell lines and for a cell line derived from normal fetal intestinal cells. All three tumor cell lines were more sensitive to OHUrd than were the FeInt cells, whereas 5-FU was more toxic to the latter. 5-Fluorodeoxyuridine was substantially more cytotoxic to only one of the tumor cell lines compared to the normal cells. In HT-29 tumor cells, OHUrd cytotoxicity could be prevented by coincubation with uridine or cytidine but not by pyrimidine deoxyribonucleosides or by purine nucleosides. Compared to OHUrd, 5-hydroxyuracil was much less cytotoxic for HT-29 cells. The increased cytotoxicity of OHUrd for these tumor cells compared to fetal intestinal cells may implicate biochemical differences that might be exploitable for improved chemotherapy. Direct comparison of drug sensitivity of colon tumor cells compared to normal counterpart cells may provide a method of screening agents selective for these tumor cells.

Selective cytotoxicity of 5-hydroxyuridine for human colon adenocarcinoma cells.

Purpose: 9-Nitrocamptothecin (9-NC) and 12-nitrocamptothecin (12-NC) are synthetic structural analogues of camptothecin (CPT) which have been prepared to explore the structure/activity relationship of this group of compounds against a wide variety of experimental tumors. As part of our investigation of the pharmacology and the mechanism of tumor inhibition of these compounds, we examined the effect of route of administration on the distribution of tritium-labeled 9-NC and 12-NC, an active and a poor chemotherapeutic agent, respectively. Methods: Quantitative whole-body autoradiography was used and our results were compared with previous results obtained with the parent compound CPT. Results: These studies revealed that, independent of the route of administration, both CPT derivatives were rapidly distributed to gall bladder, gastrointestinal tract and kidney. The excretion from these organs was indicated by the high levels of radioactivity in urine (urinary bladder) and feces (large intestines). The studies also indicated that the distributions of 9-NC and 12-NC were qualitatively similar, but quantitatively higher uptake of radioactivity was observed in animals treated with 12-NC than in those treated with 9-NC at 30 min following treatment. With the exception of the late sampling time (12 h after administration), the accumulation of radioactivity in the lungs (bronchioles) of animals that received an intravenous (i.v.) dose of 9-NC or 12-NC was higher than those treated with an intramuscular (i.m.) dose. However, the retention of drug-derived radioactivity in the tumors of mice treated with an i.m. dose of 9-NC was higher than that in the tumors of i.v.-treated animals and was also higher than that in tumors of animals treated with 12-NC. Conclusions: These results suggest that higher accumulation of 9-NC in tumor tissues than of 12-NC may contribute to the more potent chemotherapeutic activity of the former agent. Our results also suggest that i.m. injection is a more effective route of administration than i.v. administration.

Comparative disposition of the antineoplastic agent 9-nitrocamptothecin and the inactive isomer 12-nitro camptothecin in CASE-bearing nude mice: effect of route of administration on tissue distribution

A method to treat cancer is described which involves alternating treatments with a topoisomerase-I inhibitor and a topoisomerase-II inhibitor. Other aspects of the invention are further described.

Alternating treatment with topoisomerase I and topoisomerase II inhibitors

Purpose. The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice. Methods. In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations. Results. The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules. Conclusion. The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Beppino C. Giovanella

Papers

Method for treating hematologic disorders with water insoluble 20 (S)-camptothecin

Selective cytotoxicity of 5-hydroxyuridine for human colon adenocarcinoma cells.

Comparative disposition of the antineoplastic agent 9-nitrocamptothecin and the inactive isomer 12-nitro camptothecin in CASE-bearing nude mice: effect of route of administration on tissue distribution

Alternating treatment with topoisomerase I and topoisomerase II inhibitors

Enhanced Lactone Stability of CZ48 in Blood Correlates to its Lack of Toxicity in Mice