5578

PRKCA

AAG6|PKC-alpha|PKCA|PRKACA;protein kinase C, alpha;PRKCA;protein kinase C, alpha

PKC-A|aging-associated gene 6|protein kinase C alpha type

17q22-q23.2

protein-coding

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase Itrial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b)establish the pharmacokinetic profile in children; and (c) document any evidenceof antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache.Symptoms occurred in ALL patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete orpartial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well asheadache, were found to be dose limiting.

The purpose of this investigation was to evaluate the expression profile of proteins involved in children with newly diagnosed acute lymphoblastic leukemia (ALL) children who are developing relapses. For this reason, the expressions of 10 proteins including proto-oncogene and tumor suppressor gene products, proliferative factors and resistance parameters in 104 initial cases of childhood ALL were analyzed and the proteins correlated with ALL patients who experienced relapses. Applying immunocytochemical assays, we found that 4 out of the 10 parameters revealed a relationship to developing relapses (Fisher's exact tests). These were the oncogene product Fos (p=0.002), the drug resistance proteins glutathione S-transferase (p=0.008) and P-glycoprotein (P-pg/MDR1) (p=0.07) and protein kinase C (p=0.01). By means of hierarchical cluster analysis, we were able to show that the patients could be separated according to their protein expression profile into clusters consisting of patients whose ALL relapsed laterand of patients who did not show relapses in the future.