�Novel Trial Design Aims to Speed Drug Development
Researchers propose a novel multi-arm trial plan that stool test various therapies simultaneously and could speed drug development in cancer.
Scientists experience gained significant insights into the biological underpinnings of cancer, merely this knowledge has non led to a leap out in the number of therapies sanctioned for clinical use. One possible ground for the slower than expected progress is the time required for clinical testing with current visitation designs.
With that issue in mind, Mahesh Parmar, Ph.D., of the Medical Research Council Clinical Trials Unit in London and colleagues modified banner clinical trial methodology so that multiple therapies or combinations lav be compared in a single trial. The new design incorporates standard phase II and phase III goals into one multiphase trial and requires fewer patients than standard trials.
In the comment, Parmar and colleagues talk about the want for fresh approaches to clinical trials, describe the new trial design in detail, and provide examples of on-going trials that use the multi-arm trial approach. "With three real examples, we hope that we get shown that such trials are practicable and commode lead to major improvements in speeding and determination making," the authors write.
Natural Chemical from Sea Sponges Induces Death in Cancer Cells via Unusual Pathway
A chemical called candidaspongiolide (CAN) inhibits protein synthesis simply also kills cancer cells by triggering caspase 12-dependent programmed cell death.
Previous reports showed that CAN preferentially killed glioma and melanoma cells in vitro, only its chemical mechanism of action was unknown.
In the electric current study, Giovanni Melillo, M.D., of the National Cancer Institute in Frederick, Md., and colleagues used molecular and cell assays to uncover the mechanism by which CAN kills cancer cells in vitro.
CAN halts protein synthesis in both normal and cancer cells but does not kill normal cells at dosages that induction cell death in the malignant cells. CAN induces cell decease by activation caspase 12 by an unusual biochemical pathway.
The investigators conclude that further tests with CAN are warranted in vitro and in animal models.
Deletion of Chromatin Remodeling Genes Leads to Leukemia in Mice
Mice deficient both copies of the Arid4A gene and one copy of the Arid4B gene develop acute myeloid leukemia (AML) and may provide an important animate being model for preleukemic and leukemic conditions.
It is well known that genetic mutations, which spay the sequence of DNA in chromosomes, can lead story to cancer. More late, researchers take found that changes in chromatin structure and activity (epigenetic changes) can lead to crab as well. The Arid4 family of genes is involved in chromosome remodeling, but their impact on leukemia was not known.
Arthur Beaudet, M.D., of Baylor College of Medicine in Houston and colleagues bred mice that lacked both copies of Arid4A and one copy of Arid4B. They monitored the animals' health through and through repeated blood cell counts and molecular tests on blood and bone bone marrow cells.
The variation mice developed a myeloproliferative disorder that resembled chronic myeloid-monocytic leukemia. The animals then progressed to AML. The pattern of disease progression in the animals resembled the course of events in humans and may indicate that the mutant mice are utilitarian models for studying how AML develops and testing potential therapeutics.
"Further study of the Arid4 gene family may advance our sympathy of the connection 'tween gene regulation, epigenetic ascendency, disease growing, and cancer formation," the authors write. "We too suggest that gene regulating by the ARID4A and ARID4B should be examined for potentiality disease-related roles, not only in human malignancies, simply also in other complex disease traits."
Mutations in the Succinate Dehydrogenase Subunit B Gene Associated with Familial Renal Cell Cancer
Individuals world Health Organization have a germline mutant in the succinate dehydrogenase subunit B (SDHB) factor presented with familial nephritic cell genus Cancer (RCC) or with bilateral RCC.
Previous inquiry suggested that germline mutations in succinate dehydrogenase genes were principally associated with the development of pheochromocytoma or paraganglioma, which are tumor syndromes that regard other tissues. Although RCC had been reported occasionally in individuals with a germline SDHB mutation, these individuals had a personal or fellowship history of pheochromocytoma or paraganglioma. Therefore, the association of mutations in succinate dehydrogenase genes with familial RCC in the absence of other tumor syndromes was unknown.
In the current study, Eamonn Maher, M.D., of the University of Birmingham in the UK and colleagues sequenced the genes encryption several of these enzymes in 68 individuals wHO had either familial RCC or bilateral RCC but who showed no evidence of phaeochromocytoma or paraganglioma.
They identified ternary individuals with germline mutations in SDHB in this population. They conclude that the mutations are associated with an increased risk of genetic RCC.
"Our findings suggest that individuals presenting with features of hereditary RCC susceptibility should be screened for germ�line SDHB mutations because surveillance for SDHB-related tumors can then be offered to mutation-positive patients and relatives," the authors write.
In an ensuant editorial, Charis Eng, M.D., Ph.D., of the Cleveland Clinic in Ohio notes that the new data confirm premature reports of an connexion between mutations in the SDHB factor and familial RCC. She thinks, however, that it is too early to conclude whether such mutations occur in the absence of tumour syndromes granted the relatively young age at which the ternary patients in Maher's study either died or were lost to follow-up and the later age of onset for pheochromocytoma or paraganglioma.
Nonetheless, the new information have clinical utility, according to Eng. "It is entirely appropriate, at this time, to counsel patients carrying SDHB mutations, espe�cially those with Arg mutations, that they have a small simply finite likelihood of development RCC," she writes.
Also in the August 26 JNCI:
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Saturday 6 September 2008
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