Small Cell Cancer of the Bladder and Prostate: A Retrospective Review from a Tertiary Cancer Center.

BACKGROUND:  Genitourinary small cell cancer (GUSCC) is a rare malignancy. Most of the published data on how to manage this malignancy is based on institutional experience. We undertook the current retrospective review to determine the outcome of the patients with GUSCC treated at CancerCare Manitoba, Canada over a period of 18 years. METHODS: The Manitoba Cancer Registry was used to identify patients with a confirmed pathological diagnosis of small cell cancer (SCC) of the bladder or prostate between January 1, 1995, and October 31, 2013. RESULTS:  There were 42 patients identified, 28 bladder SCC (17 limited, 11 extensive stage) and 14 prostate SCC (one limited, 12 extensive, and one unknown stage). The median age was 70.7 years. There were 22 patients who were treated with chemotherapy and radiation, five received radiation only, four received chemo only, nine did not receive any treatment, one patient had surgery only, and one had surgery and radiation. The median and one-year overall survival for all patients was 10.7 months and 43%. The median and one-year overall survival of SCC of the bladder was 55.1 months and 71% for the limited stage and 10.1 months and 36% for the extensive stage. The median and one-year overall survival for extensive stage SCC of the prostate was 4.1 months and 17%. There was only one patient with limited stage SCC of the prostate who did not receive any treatment and died of progressive disease 11 months from diagnosis. CONCLUSIONS:  Our findings suggest that patients with limited stage SCC of the bladder can have a surprisingly good outcome with multimodality treatment. The outcome of the patients with extensive stage SCC of the bladder and prostate remains dismal and optimal therapeutic options have yet to be determined.

Brevinin-2R(1) semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway.

Brevinin-2R is a novel non-hemolytic defensin that was isolated from the skin of the frog Rana ridibunda. It exhibits preferential cytotoxicity towards malignant cells, including Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), HT29/219, SW742 (colon carcinomas), L929 (fibrosarcoma), MCF-7 (breast adenocarcinoma), A549 (lung carcinoma), as compared to primary cells including peripheral blood mononuclear cells (PBMC), T cells and human lung fibroblasts. Jurkat and MCF-7 cells overexpressing Bcl2, and L929 and MCF-7 over-expressing a dominant-negative mutant of a pro-apoptotic BNIP3 (DeltaTM-BNIP3) were largely resistant towards Brevinin-2R treatment. The decrease in mitochondrial membrane potential (DeltaPsim), or total cellular ATP levels, and increased reactive oxygen species (ROS) production, but not caspase activation or the release of apoptosis-inducing factor (AIF) or endonuclease G (Endo G), were early indicators of Brevinin-2R-triggered death. Brevinin-2R interacts with both early and late endosomes. Lysosomal membrane permeabilization inhibitors and inhibitors of cathepsin-B and cathepsin-L prevented Brevinin-2R-induced cell death. Autophagosomes have been detected upon Brevinin-2R treatment. Our results show that Brevinin-2R activates the lysosomalmitochondrial death pathway, and involves autophagy-like cell death.

The emerging importance of DNA mapping and other comprehensive screening techniques, as tools to identify new drug targets and as a means of (cancer) therapy personalisation.

Every human being is genetically unique and this individuality is not only marked by morphologic and physical characteristics but also by an individual's response to a particular drug. Single nucleotide polymorphisms (SNPs) are largely responsible for one's individuality. A drug may be ineffective in one patient, whereas the exact same drug may cure another patient. Recent advances in DNA mapping and other screening technologies have provided researchers and drug developers with crucial information needed to create drugs that are specific for a given individual. In the future, physicians will be able to prescribe individualised drugs adjusted to, for example, activities of specific enzymatic pathways that would either be targeted by these drugs, or would be responsible for drug conversion or inactivation. Furthermore, the mapping of the human genome allows broader development and application of drugs that act on the level of gene transcription rather than as simple biochemical inhibitors or activators of certain enzymes. Such new approaches will maximise desired therapeutic results and may completely eliminate severe side effects. To illustrate the potential of genetic translational research, the authors discuss available analytical methodologies such as; gene arrays, flow cytometry-based screening for SNPs, proteomics, metabolomics, real-time PCR, and other methods capable of detecting both SNPs, as well as more profound changes in cell metabolism. Finally, the authors provide several examples that focus mostly on targeting protein-DNA interactions, but also other processes.

Caspases and cancer: mechanisms of inactivation and new treatment modalities.

Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis. Deregulation of apoptotic signaling pathways may contribute to oncogenesis. Aspartate specific cysteine proteases, termed caspases are the key effector molecules in apoptosis. The aim of this review is to summarize the various defects in caspase-dependent cell death machinery identified in the neoplastic cells. These include not only mutations, but also alterations of gene methylation, and altered mRNA stability. Among the molecules that we discuss are elements of the extrinsic death pathway like CD95 (APO-1/Fas), FADD, FLIPs, FLICE, other apical caspases, components of the intrinsic apoptotic pathway like Apaf-1, caspase-9, and modulators of apoptotic pathways like IAPs, Smac/DIABLO, OMI/HtrA2, and other apoptosis regulating proteins. We also discuss recent data on cancer-specific agents that target effector mechanisms of apoptosis. Particular emphasis is given to the prospects for combining cell suicide-activating approaches with classical cancer therapies.