This comparison yielded Pearson correlation coefficients of 0. 96 and 0. 97

Modest effects were observed in advanced renal cell cancer and ARQ 197 gastric esophageal cancer, but the overall response was disappointing and more than half of the patients experienced severe myalgias, necessitating early termination of one study131 134. Aprinocarsen, an anti sense oligonucleotide that targets PKC mRNA, has also been studied clinically in a number of oncology trials. In phase 2 studies, aprinocarsen failed to show activity as a single agent against advanced colorectal, ovarian, and hormone refractory prostate cancer135 138 and showed only modest activity against relapsed, low grade non Hodgkins lymphoma139. In two phase 3 non small cell lung cancer studies, aprinocarsen failed to improve tumor response rate or survival when added to combination chemotherapy, but additional toxicities including thrombocytopenia and venous thromboembolism were observed140,141.<br><br> Further clinical development of aprinocarsen has been discontinued. Enzastaurin is an orally available small molecule selective inhibitor of PKCB that targets the ATP binding site. Single agent phase 2 studies showed inadequate efficacy AUY922 ic50 in patients with advanced presentation of the following malignancies: large B cell lymphoma, mantle cell lymphomas, non small cell lung cancer, high grade gliomas, recurrent ovarian and primary peritoneal malignancies, and asymptomatic chemotherapy na ve colorectal cancer142 147. In a larger phase 2 study, enzastaurin did not add to the anti tumor activity of pemetrexed and carboplatin in patients with stage IIIb or stage IV non small cell lung cancer148.<br><br> Clinical studies are ongoing to assess the addition of enzastaurin to combination chemotherapy for advanced brain malignancies. Other PKC modulators have undergone limited study in oncologic indications. High dose tamoxifen provided negligible benefit to patients with malignant gliomas and hormone refractory prostate cancer149 151. Midostaurin, Alvocidib 146426-40-6 an orally available multi targeted kinase inhibitor had no effect against malignant melanoma in a small study152. Midostaurin did show 50% reduction in blast counts in a substantial proportion of patients with acute myeloid leukemia and myelodysplastic syndrome and is being assessed in clinical trials for hematologic malignancies, but its effect may be mediated by FMS like tyrosine kinase 3, which is mutated and constitutively overactive in up to 30% of patients with myeloid leukemias153.<br><br> UCN 01, a non selective kinase inhibitor, was ineffective against both progressive renal and ovarian cancers154,155. Cardiovascular Trials Flosequinan, a non selective inhibitor of inositol triphosphate and PKC, was compared to placebo in 193 patients with symptomatic heart failure. After 12 weeks, patients in the flosequinan group showed statistically significant improvements in maximal treadmill exercise time, increase in maximal oxygen consumption, and symptom improvement 156. In a larger subsequent study, the Data Monitoring Committee stopped the trial prematurely after an interim analysis revealed increased deaths and hospitalizations in the active arm, and flosequinan was removed from the market157.