Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non-small cell lung cancer.

Gemcitabine is a fluoridated pyrimidine related to cytosine arabinoside that has significant activity in solid tumor models. Irinotecan is a camptothecin analog with an active metabolite, SN-38, which inhibits topoisomerase I activity by stabilizing the topoisomerase I-DNA cleavable complex. Gemcitabine studies in non-small cell lung cancer conducted in the United States, as well as an international collaboration and clinical trials from Europe and Japan, found overall response rates of 20% to 26%, a median duration of response between 5 to 9 months, and a median duration of survival ranging from 7 to 12.3 months. Gemcitabine also has been shown to be more effective than best supportive care in non-small cell lung cancer. In a phase I trial of irinotecan (50, 75, 100, and 115 mg/m2) in combination with 1,000 mg/m2 gemcitabine, three patients had documented partial responses: one with pancreas cancer at irinotecan 100 mg/m2, one with pancreas cancer, and one with metastatic carcinoma of unknown primary at irinotecan 115 mg/m2. Three of five non-small cell lung cancer patients had stable disease for four or more cycles at irinotecan doses of 50, 75, and 100 mg/m2; no non-small cell lung cancer patients were treated at irinotecan 115 mg/m2. We recommend that a combination of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given on days 1 and 8 every 3 weeks be used as the starting dose in future phase II studies. Furthermore, based on the absence of severe nonhematologic toxicity or grade IV hematologic toxicity in the majority of patients treated at the highest dose, escalation of irinotecan to 115 mg/m2 may be considered for subsequent cycles in patients who do not experience > or =grade I hematologic or non-hematologic toxicity during the first cycle of gemcitabine/irinotecan combination chemotherapy.

Sequence and comparative analysis of the genome of HSV-1 strain McKrae.

Ocular infection by HSV-1 strain McKrae is neurovirulent in both mice and rabbits and causes fatal encephalitis in approximately 50% of animals. In addition, it spontaneously reactivates with high frequency relative to other HSV-1 strains in rabbits. We sequenced the McKrae strain genome and compared its coding protein sequences with those of six other HSV-1 strains. Most of the 74 predicted protein sequences are conserved; only eleven are less than 98% conserved. Eight proteins were identified to be unique for McKrae based on sequence homology bit score ratio (BSR). These include five proteins showing significant variations (RL1, RS1, UL49A, US7 and US11), two truncated proteins (UL36 and UL56) and one (US10) containing an extended open reading frame. The McKrae strain also has unique features in its 'a' sequence and non-coding sequences, such as LAT and miRNA. These data are indicative of strain variation but need further work to connect observed differences with phenotype effects.

Plasma volume and ion regulation during exercise after low- and high-carbohydrate diets.

This study compared plasma volume (PV) and ion regulation during prolonged exercise in control vs. glycogen-depleted (GD) conditions, with emphasis on the initial minutes of exercise. In two trials separated by 1-2 wk, four adult males cycled at 75% of peak oxygen consumption (VO2) until exhaustion (50 +/- 7 min for GD) or until the GD exhaustion time in the control trial. Blood was sampled from catheters placed in the brachial artery and retrograde in the femoral vein (fv). Arterial PV decreased rapidly and by 15 min PV was 83% (control) and 88% (GD) of initial. The decrease in PV was accompanied by a net osmotic flux of water from plasma and inactive tissues to contracting muscles. The significantly greater decrease in PV in control compared with GD was associated with a higher muscle lactate content (Lac-; 36 vs. 17 mumol/g dry wt, respectively). Increases in plasma [Cl-] and [Na+] were less than predicted from decreased PV, indicating net loss of these ions from the plasma compartment. Increases in arterial and fv [K+] were 50% greater than could be accounted for by decreased PV, corresponding with increased arterial and fv plasma K+ contents. The rapid net release of K+ and Lac- from contracting muscle during the first few minutes of exercise in both trials was abolished (control) or reversed (GD) within 15 min of beginning exercise.(ABSTRACT TRUNCATED AT 250 WORDS)