Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive lowdose MTX (LDMTX: 6 oral doses of 30 mg/m 2 ) or high-dose MTX (HDMTX: intravenous 1 g/m 2 ) followed by intravenous MP; or intravenous MP alone (1 g/m 2 ), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 ؎ 189 vs 250 ؎ 38 fmol/nmol/h; P ‫؍‬ .001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P < .001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (؊50% ؎ 4%, ؊56% ؎ 3%, and ؊ 20% ؎ 4%, respectively; P < .0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (؊63% ؎ 4% vs ؊37% ؎ 4%; P < .0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL.HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 ؎ 298 vs 1075 ؎ 114 pmol/ 10 9 cells; P < .01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P < .001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after

ABSTRACT. Objective. The purpose of this study was to compare the incidence of nephrotoxicity, defined as doubling of baseline serum creatinine concentration, in newborn infants with peak vancomycin serum concentrations <40 g/mL at steady state to infants with peak vancomycin serum concentrations >40 g/mL. A secondary objective was to correlate concomitant disease states and potentially nephrotoxic drug therapy with rises in serum creatinine in vancomycin recipients.Methods. Newborn infants with culture-proven Staphylococcus aureus or coagulase-negative staphylococcal septicemia who received vancomycin therapy for >3 days between 1985 and 1995 were identified from an existing database and a review of medical record. All 69 patients included in the study had serial serum creatinine determinations, including a baseline value within 48 hours of starting treatment with vancomycin, and serum vancomycin concentrations determined after at least three doses, with peak and trough concentrations determined 1 hour after a 60-minute infusion and 15 to 30 minutes before a dose, respectively. Infants with congenital renal or cardiac anomalies were excluded. Demographic characteristics, vancomycin dosing regimen, serum vancomycin concentrations and sample times, concomitant drug therapy, and disease states were recorded. Patients were divided into group A (peak vancomycin concentration <40 g/mL) and group B (peak vancomycin concentration >40 g/mL). The change in serum creatinine concentration between the start and end of vancomycin therapy was determined. Nephrotoxicity was identified if serum creatinine doubled at any time from the start to the end of vancomycin therapy. Alternative definitions of nephrotoxicity (any rise in serum creatinine to >0.6 mg/dL or new abnormalities of urine sediment) were used in additional analyses.Results. A total of 69 evaluable patients (gestational age, 28.9 ؎ 3.0 weeks; birth weight, 1219 ؎ 516 g) were identified, 61 in group A and 8 in group B. Six patients in group A underwent doubling of serum creatinine concentration during vancomycin therapy, whereas none in group B did so. Serum creatinine doubled to >0.6 mg/dL in only 3 infants (all in group A). Any increase in serum creatinine to >0.6 mg/dL was seen in 10 infants, 9 of whom were in group A. No confounding variable, including previous or concomitant underlying disease states associated with renal dysfunction or treatment with other potentially nephrotoxic agents, were associated with a significant rise in serum creatinine.Conclusion. Vancomycin-associated nephrotoxicity is rare in neonates, even with serum peak concentrations >40 g/mL. Pediatrics 1999;103(4). URL: http://www.pediatrics. org/cgi/content/full/103/4/e48; vancomycin, nephrotoxicity, newborn infants, NICU, Staphylococci, creatinine, renal, antibiotics.

The amount of MSH2 protein, a major component of the mismatch repair system, was found to differ Ͼ10-fold in leukemia cells from children with newly diagnosed acute lymphoblastic leukemia, with a subgroup of patients (17%) having undetectable MSH2 protein. We therefore used a murine Msh2 knockout model to elucidate the in vivo importance of MSH2 protein expression in determining thiopurine hematopoietic cytotoxicity. After mercaptopurine (MP) treatment (30 mg/kg/day for 14 days), there was a significantly greater decrease in circulating leukocytes in Msh2

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