Patients with a glioblastoma containing a methylated MGMT promoter (gene silencing) benefited from temozolomide (Temodar), whereas those who did not have a methylated MGMT promoter did not have such a benefit.
Molecular genetic analysis of loss of heterozygosity (LOH of 1p) and MGMT promoter methylation were associated with long progression-free survival. LOH of 1p in the heterogeneous population of malignant gliomas may be one of the important factors besides MGMT methylation that predict better outcome in patients treated with Temodar.
http://www.ncbi.nlm.nih.gov/pubmed/17721049
I think that functional, cell culture-based assays would be vastly more informative for Temodar and virtually all drugs than marker-based tests, including multi-gene tests. It would include anti-vascular drugs, such as bevacizumab (Avastin), sunitinib (Sutent), sorafenib (Nexavar), erlotinib (Tarceva), gefitinib (Iressa), lapatinib (Tykerb), imatinib (Gleevec), Tamoxifen, Thalidomide, both as single agents and in combination with each other and with traditional cytotoxic agents.
It can provide more valuable information today than will be provided with marker and genomic based assays 10 years from now. It can simultaneously test for direct anti-tumor activity and for antivascular activity against the microvascular present within the three dimensional tumor cell clusters.
I believe that the short term future of cancer therapeutics is combinations of "targeted" agents.
http://weisenthalcancer.com/Professionals%20Pages/EGFRxProfessionals.htm
There has been developed a new bio-marker assay (AngioRx™) for microvascular viability to identify potential responders to Avastin, Nexavar, Sutent, and other anti-angiogenic drugs by targeting not the cells themselves, but rather VEFG secreted by tumor cells, and to assess previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva and Iressa.
Prior to development of the AngioRx™ assay it was thought that the lack of an intact tumor micro-vasculature would prevent in vitro drug studies in disaggregated tissues. However, it was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in this microvascular assay.
The principles and methods used in the microvascularity viability assay include:
1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient.
2. Exposing viable tumor cells to anti-neoplastic drugs.
3. Measuring absolute in vitro drug effect.
4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity.
5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.
It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.
Photomicrographs in the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The assay measures the net effect of everything which goes on (Functional Tumor Cell Profiling). Are the cells ultimately killed, or aren't they?
http://weisenthalcancer.com/Professionals%20Pages/AngioRxProfessional.htm
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