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...

/pdf/idh1-and-idh2-mutations-in-gliomas-1er88anbwg.pdf

IDH1 and IDH2 Mutations in Gliomas

p53, guardian of the genome

Studies of time/dose intensity in treatment of human cancer xenografts with camptothecin analogues

Camptothecin (CPT) inhibits the growth of a wide variety of experimental tumors. As a part of our exploration of this drug for use as a cancer chemotherapeutic agent, we studied the effect of route of administration on the absorption, distribution and tumor uptake of [3H]-CPT. The rate of disappearance of [3H]-CPT-derived radioactivity from blood during the first 48 h was highest following oral than following intravenous (i.v.) administration. Thereafter blood levels were low irrespective of route of administration. Considerable [3H]-CPT-derived radioactivity was detected in urine and feces up to 48 h after dosing. Distribution studies were conducted using quantitative whole-body autoradiography (WBA). These studies revealed that independent of the route of administration, [3H]-CPT was rapidly excreted in the bile (gallbladder) followed by elimination into the small and large intestinal tract. Levels of CPT-derived radioactivity in the kidneys were minimal and mostly localized in the renal pelvis. Hepatic concentrations of CPT were low and were almost equal to those of the tumor. The lungs of animals treated i.v. showed higher uptake of radioactivity than those treated intramuscularly or orally. Tumor/blood ratios were slightly higher following oral administration than following administration by other routes. This study indicates that CPT is primarily eliminated via the bile. The gastrointestinal tract is the major site of accumulation and excretion of CPT.

Influence of route of administration on [3H]-camptothecin distribution and tumor uptake in CASE-bearing nude mice: whole-body autoradiographic studies.

Cell sublines resistant to doxorubicin (DOX) were developed from the human leukemia cell line, U-937/WT, exposed to stepwise DOX increases. In contrast to U-937/WT cells, the DOX-resistant U-937/RD cells have longer doubling time; are more differentiated along the monocytic lineage as determined by the presence of morphological features and mRNA coding for the monocyte colony-stimulating factor-1 receptor; synthesize the apoptosis-associated Bax protein; are less sensitive to apoptosis-inducing topoisomerase II-directed drugs, apparently because of increased synthesis of P-glycoprotein; and are practically non-tumorigenic when xenografted in nude mice. However, U-937/WT and U-937/RD cells exhibit similar sensitivity to the apoptosis-inducing drug 9-nitrocamptothecin. These findings suggest that several mechanisms are involved in the development of DOX-resistance in U-937 cells, and further, 9-nitrocamptothecin can overcome resistance to DOX. These findings may have clinical implications.

Development of human leukemia U-937 cell sublines resistant to doxorubicin: induction of differentiation and altered sensitivities to topoisomerase-directed drugs.

We have recently reported that exposure of human leukemia U-937 cells to progressively increasing concentrations of 9-nitro-camptothecin (9NC) resulted in cell sublines exhibiting various levels of resistance to 9NC. Here, we report responses of wild-type (U-937/wt) and 9NC-resistant (U-937/CR) cells to various anticancer drugs used extensively in cancer chemotherapy. U-937/CR cells were more sensitive than U-937/wt cells to several commonly used drugs of diverse origin including the topoisomerase II-directed drugs amsacrine, etoposide and daunorubicin; the vinca alkaloid vincristine; and the antimetabolite methotrexate. No responses were induced by carmustine in either cell type, whereas similar responses were induced by cytarabine. The sensitivity to the drugs was investigated by monitoring cell proliferation, by determining cell cycle perturbations assessed by flow cytometry analysis of DNA content and by microscopy of stained cells. The results in this report indicate that development of 9NC resistance by the U-937 cells is accompanied by increased sensitivities to other anticancer drugs in vitro and very likely in vivo.

Development of resistance to 9-nitro-camptothecin by human leukemia U-937 cells in vitro correlates with altered sensitivities to several anticancer drugs.

A method of treating human pancreatic cancer with water-insoluble 20(S)-camptothecin compounds with the closed-lactone ring intact and/or derivatives thereof is disclosed. The method includes preferably administering the compounds intramuscularly, orally, and transdermally.

Beppino C. Giovanella

Papers

Studies of time/dose intensity in treatment of human cancer xenografts with camptothecin analogues

Influence of route of administration on [3H]-camptothecin distribution and tumor uptake in CASE-bearing nude mice: whole-body autoradiographic studies.

Development of human leukemia U-937 cell sublines resistant to doxorubicin: induction of differentiation and altered sensitivities to topoisomerase-directed drugs.

Development of resistance to 9-nitro-camptothecin by human leukemia U-937 cells in vitro correlates with altered sensitivities to several anticancer drugs.

Method for treating pancreatic cancer in humans with water-insoluble S-camptothecin of the closed lactone ring form and derivatives thereof