Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple genetic alterations such as in Ras or EGFR can result in sustained signaling through PI3K. Our previous experiments have shown that resistance to radiation results from PI3K activity in cells in culture. Here we examined whether inhibition of PI3K in vivo would sensitize tumors to radiation. The human bladder cancer cell line T24 has amplified and mutated H-Ras resulting in sustained PI3K activity and phosphorylation of the downstream target of PI3K, Akt. Nude mice bearing T24 tumor cell xenografts were randomly assigned to one of four groups: control, radiation alone, the PI3K inhibitor LY294002 alone, or combined LY294002 and radiation. The LY294002 was delivered intraperitoneally to the mice. Downregulation of Akt was documented by Western blot analysis of tumor lysates. In vivo sensitization was measured using clonogenic assays or regrowth assays.A dose of 100 mg/kg of LY294002, but not 50 mg/kg, consistently eliminated the phosphorylation of Akt. This inhibition was transient, and Akt activity returned after 30 min. This dose resulted in severe respiratory depression and lethargy resolving without lethality. It is not possible to tell whether these side effects of LY294002 were mechanism-based or idiosyncratic. The PI3K inhibitor LY294002 by itself had minimal antitumor effect. The combination of LY294002 and radiation resulted in significant and synergistic reduction in clonogenicity and growth delay. Inhibition of PI3K by LY294002 can synergistically enhance radiation efficacy. This acts as a proof of principle that inhibition of the Ras to PI3K pathway could be useful clinically.
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PMID:Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. 1278 94

Erlotinib (Tarceva) is a selective small-molecule inhibitor of HER1/EGFR tyrosine kinases that is especially effective for treating non-small cell lung cancer (NSCLC) harboring a constitutively active EGFR mutation. Erlotinib treatment frequently induces adverse effects such as skin rashes and diarrhea, but severe toxicity is rare. Whereas interstitial pneumonia induced by erlotinib is sometimes observed, toxicity in the central nerve system (CNS) is rarely reported. Here, we report a 75-year-old female NSCLC patient who developed subacute encephalopathy during erlotinib treatment. She showed increased irritability, loss of consciousness, convulsions, confusion, lethargy, and urinary incontinence. A brain MRI and an analysis of her CSF and blood serum detected no other causes of encephalopathy such as brain metastasis, leptomeningeal carcinomatosis, metabolic disturbances, liver damage, or infectious disease. Her subacute encephalopathy was considered to have been induced by erlotinib because her symptoms improved rapidly and spontaneously after the cessation of erlotinib treatment.
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PMID:Subacute transient encephalopathy induced by erlotinib. 2232 99