Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib

We aimed to determine whether patients receiving dasatinib or imatinib concurrently with high‐dose methotrexate (HDMTX) had slower methotrexate clearance than patients not receiving a tyrosine kinase inhibitor (TKI) during the HDMTX infusion. Patients concurrently receiving dasatinib and HDMTX (N = 7) had significantly slower MTX clearance (P = 0.008) than patients not receiving a TKI (N = 111). Two patients receiving a TKI during a HDMTX infusion required glucarpidase. In vitro studies showed that dasatinib significantly inhibited methotrexate uptake by SLCO1B1‐expressing cells (P = 0.009). There may be an interaction between dasatinib and HDMTX, mediated by the transporter SLCO1B1, that causes a delay in MTX clearance.     

High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

BACKGROUND: The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. PROCEDURE: Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. RESULTS: Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. CONCLUSIONS: These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.     

Prognostic significance of chemotherapy dosage characteristics in children with osteogenic sarcoma

High-dose methotrexate (HDMTX), adriamycin (ADR), and cisplatinum (CDDP) are effective agents in the treatment of osteogenic sarcoma (OS). Individual patient doses are determined by prior successful clinical trials but may be reduced due to ongoing toxicities. It is unknown whether individualized dose reductions of these drugs influence disease outcome. We retrospectively studied 27 consecutively enrolled children treated with HDMTX, ADR, and CDDP as adjuvant chemotherapy for OS, for correlations between disease outcome and several characteristics of drug, dosing: the cumulative MTX, CDDP, and ADR doses administered and the mean MTX blood levels for each patient. With a median follow-up of 59 months, the actuarial overall and disease-free survival rates were 70% and 59%, respectively. Factors which favorably influenced prognosis on univariate analysis were a cumulative ADR dose of >300 mg/m² (P = 0.0002) and a cumulative MTX dose > 114 gm/m² (P = 0.0048). By multivariate analysis only the cumulative ADR dose >300 mg/m² retained prognostic value. We conclude that adjuvant chemotherapy dosages may need to be adjusted for therapeutic efficacy in addition to adjustments made for toxicity. The effect of different cumulative HDMTX and ADR dosages on prognosis in osteosarcoma patients needs to be evaluated in a prospective trial. Med. Pediatr. Oncol. 28:179–182 © 1997 Wiley-Liss, Inc.     

尿神经导向因子-1和肾损伤分子-1对窒息后新生儿急性肾损伤的诊断价值探讨

目的 分析尿神经导向因子-1(Netrin-1)和肾损伤分子-1(Kim-1)的变化对新生儿窒息引起的急性肾损伤(AKI)的早期诊断价值。方法 选取足月窒息新生儿80 例(轻度窒息组34 例,重度窒息组46 例),以及正常足月新生儿40 例(无窒息组)。分别收集三组新生儿出生后12 h、13~48 h 内尿标本,采用酶联免疫法(ELISA)检测尿Netrin-1 及Kim-1 的水平,同时抽取外周静脉血检测血肌酐(Scr)水平。结果 窒息组患儿生后48 h 内的尿Netrin-1 及Kim-1 水平明显高于无窒息组,生后13~48 h 内的Scr 水平高于无窒息组(P<0.05);AKI 组患儿生后48 h 内的尿Netrin-1、Kim-1、Scr 均高于非AKI 组(P<0.05);12 h 内的尿Netrin-1、Kim-1 预测窒息后AKI 的AUC 值分别为0.878(95%CI 0.775~0.981,P<0.01)和0.899(95%CI 0.829~0.969,P<0.01);新生儿窒息后12 h 内的尿Netrin-1、尿Kim-1、Scr 分别呈明显正相关(P<0.05)。结论 窒息新生儿发生AKI时尿Netrin-1 和Kim-1 水平明显增高;尿Netrin-1 和Kim-1 可作为早期判断窒息后AKI 的指标。     

Association of ABCC2 with levels and toxicity of methotrexate in Malaysian Childhood Acute Lymphoblastic Leukemia (ALL)

Abstract

Studies had shown that genetic polymorphism plays a significant role in the pharmacokinetics and pharmacodynamics variation of high dose methotrexate (MTX), 5000?mg/m² regimen. The objective of this study was to investigate the genetic variations associated with the serum level and toxicity of MTX in Malaysian children with acute lymphoblastic leukemia (ALL). Thirty-eight patients were genotyped for rs717620 (ABCC2), rs4948496 (ARID5B), rs1801133 (MTHFR) and rs4149056 (SLCO1B1). Serum levels of MTX at 48?h post 24?h of intravenous infusion were analyzed by high-performance liquid chromatography-mass spectrometry. The ABCC2 genotype was significantly associated with the serum levels of MTX at 48?h after treatment (p?=?0.017). Patients with CT and TT of rs717620 (ABCC2) and TC and CC of rs4948496 (ARID5B) were significantly associated with leukopenia grade I–IV (Fisher Exact Test; p?=?0.03 and 0.02, respectively). The three most common MTX related toxicities were leukopenia (60.5%), increased alanine aminotransferase enzyme (47.4%), and thrombocytopenia (47.4%). Our results demonstrate that by prescreening of patients for ABCC2 and ARID5B associated with the serum levels and adverse effects of MTX would identify patients at risk and therefore help a pediatric oncologist to personalize chemotherapy drugs for precision health.     

Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved setting is feasible, safe, and cost-effective

Background

We describe the safety, feasibility, and provide a cost‐estimate of outpatient high‐dose methotrexate administration (HDMTX) among an urban, underserved population.

Procedure

A retrospective analysis of ambulatory HDMTX administration among osteosarcoma patients, at Montefiore Medical Center's Children's Hospital (Bronx, NY) was performed. HDMTX (12 g/m²) was given intravenously (IV) over 4 hr after urine alkalinization. Patients were discharged home to continue IV hydration and alkalinization delivered via a home infusion pump. Families were instructed to monitor urine pH overnight and management was adjusted according to our institution's treatment algorithm until MTX level ≤0.1 µmol/L. A cost estimate was performed to assess the difference in costs for outpatient versus hypothetical inpatient administrations.

Results

Of the 97 ambulatory HDMTX administrations, 99% were successfully completed. One patient failed outpatient administration secondary to home infusion pump malfunction. This patient successfully completed subsequent courses as an outpatient. Most patients (72%) had a MTX level of <10 µmol/L at 24 hr post‐HDMTX. No patients were found to have a MTX level of >50 µmol/L at 24 hr. About 26% of courses were associated with grade III or IV neutropenia, 4% were associated with grade III or IV thrombocytopenia and 1% were associated with grade III/IV leukopenia. Compared to a hypothetical hospital inpatient stay, the hospital costs for ambulatory HDMTX were an average of $1400 less per cycle.

Conclusion

Ambulatory HDMTX administration among an underserved, urban population is safe, feasible, and cost‐effective. Pediatr Blood Cancer. 2010;55:1296–1299. © 2010 Wiley‐Liss, Inc.     

急性淋巴细胞白血病患儿亚甲基四氢叶酸还原酶基因多态性与大剂量甲氨蝶呤不良反应的相关性

目的探讨急性淋巴细胞白血病(ALL)患儿亚甲基四氢叶酸还原酶(MTHFR)基因677位点多态性与大剂量甲氨蝶呤(HDMTX)体内排泄及不良反应的相关性。方法 2008年3月-2010年2月在本院儿科中心和血液内科住院的完全缓解并接受HDMTX治疗的40例ALL患儿,在接受HDMTX治疗前应用PCR-限制性酶切片段长度多态性(RFLP)技术检测MTHFR基因C677T多态性,在HDMTX静脉输注开始后24 h、48 h应用荧光偏振免疫法(FPIA)测定其血浆MTX水平,密切观察ALL患儿HDMTX化疗后的不良反应,对化疗不良反应进行分级。对MTHFR677的基因多态性与MTX不良反应及HDMTX 48 h的MTX水平(MTX-48 h)的相关性进行分析。结果在有HDMTX相关不良反应的ALL患儿中,肝损害和骨髓抑制发生率最高。MTHFR C677T有肝脏损害的基因型分布频率由低到高为CC型40.0%,TT型60.0%,CT型80.0%,CT基因型者肝脏损害发生的风险是CC基因型者的6倍(OR=6.00,95%CI:1.05～34.32,P=0.044);677CT+TT基因型者肝脏损害发生的风险是CC基因型者的4.13倍(OR=4.13,95%CI:1.02～16.67,P=0.047)。MTHFR C677T基因型与骨髓抑制无明显相关性。携有MTHFR突变基因型(CT+TT)患者的48 hMTX血药质量浓度明显高于携带MTHFR野生型基因CC者(P=0.006)。结论 MTHFR 677位基因型可作为ALL患儿HDMTX化疗不良反应和药物体内排泄的有效预测指标。     

缺氧缺血性脑损伤新生大鼠松果体miRNA-182及Clock mRNA的表达变化

目的观察新生大鼠缺氧缺血性脑损伤(HIBD)后松果体内小RNA(miRNA)的差异表达,研究其在HIBD导致的昼夜节律紊乱中的作用。方法将7日龄的新生Sprague-Dawley(SD)大鼠随机分为HIBD模型组和假手术组,根据Rice-Vannucci法制作HIBD模型,24h后分别取两组松果体组织,通过miRNA芯片检测及实时荧光定量PCR法(RT-PCR)筛选出HIBD后高表达的miRNA,测定其在各组织(肺、肠、胃、肾、大脑皮层、松果体组织)中的表达差异。利用RT-PCR技术分别测定两组在缺氧缺血后0、24、48、72h松果体中高表达miRNA及靶基因Clockm RNA的表达变化。结果 miRNA芯片结果结合RT-PCR技术筛选出多个和HIBD相关的miRNA,其中miRNA-182表达差异明显。miRNA-182在松果体组织中高丰度表达。HIBD后24h、48hmiRNA-182的表达水平高于对应时间点的假手术组(P0.05);与对应时间点的假手术组相比,HIBD后0hClockm RNA表达水平升高,48h时降低,72h后明显升高(P0.05)。结论 miRNA-182可能参与了HIBD后昼夜节律紊乱的病理生理过程。     

Methotrexate levels and outcome in osteosarcoma

BACKGROUND: Peak serum concentrations of methotrexate (MTX) have been reported to correlate with outcome in osteosarcoma (OS). Modification of the MTX dose to achieve peak levels between 700 and 1,000 micromol/L has been recommended. The goal of the study was to assess whether there is a correlation between histologic necrosis of the tumor and/or prognosis with peak MTX serum concentration. PROCEDURE: Treatment included multi-agent adjuvant chemotherapy, including high-dose MTX (12 g/m2). Peak MTX levels were drawn following a 4-hr infusion. Histologic evaluation for percent necrosis was done at the time of definitive resection. RESULTS: The median peak MTX level (n = 52 patients) was 1,060 micromol/L (range: 410-4,700 micromol/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 micromol/L or higher. Response to pre-operative chemotherapy was: 18% Grade I necrosis, 35% Grade II, 31% Grade III, and 16% Grade IV. No significant association was found between the mean peak MTX levels and necrosis (P = 0.44). Event-free survival (EFS) for the 48 patients with non-metastatic disease at diagnosis was 76% at 4 years of follow-up, with no association between the mean peak MTX level and EFS (P = 0.24). CONCLUSIONS: The absence of a demonstrable correlation between peak MTX levels and histologic necrosis or EFS may suggest that most patients achieve therapeutic levels when MTX is given at a dose of 12 g/m(2). The significant degree of intra-patient variability in peak levels poses a dilemma for pharmacokinetic adjustment. Continued use of HD-MTX in all patients, rather than dose adapted therapy, may be justified.     

How long can folinic acid rescue be delayed after high‐dose methotrexate without toxicity?

To determine the optimal time of folinic acid rescue after methotrexate (MTX) treatment in patients with ALL, we selected and evaluated relevant studies that included doses, rescue delay, and side effects. Rescue at 42–48 hours resulted in considerable toxicity, except when low doses of MTX were used (1 g/m²) or serum MTX levels remained consistently low at 24, 30, and 36 hours. Rescue started at 30–36 hours was safe. In the absence of evidence that later rescue improves prognosis, we suggest that folinic acid rescue (105 mg/m²) be started no later than 36 hours from the start of MTX (5–6 g/m²). Pediatr Blood Cancer 2014;61:7–10. © 2013 Wiley Periodicals, Inc.     

Magnesium therapy in birth asphyxia

Objective: Glutamate plays a critical role in the hypoxic ischaemic neuronal death. Two mechanisms of glutamate-induced neuronal death have been identified. One is rapid cell death that occurs in minutes and the second is delayed cell death that occurs over hours and is initiated principally by the activation of the N-methyl D-Aspactate (NMDA) receptor. Magnesium (Mg) is an NMDA receptor blocker. Systemic administration of Mg after a simulated hypoxic ischaemic insult has been shown to limit neuronal injury in several animal models. However, before embarking on to the use of Mg for neuronal protection in the human neonate, it is important to study the safety and side effects of Mg administration.Methods: Forty terms, appropriate for gestational age babies with severe birth asphyxia (1 min Apgar score <3 and 5min Apgar score <6), were randomly assigned to either the study group or the control group. Infants in both groups were treated as per unit protocol except that babies in the study group received intravenous injection of magnesium sulphate 250 mg/kg within half an hour of birth, and subsequently 125 mg/kg at 24 and 48 hours of life.Results: The mean cord blood serum Mg levels were 0.78 (±0.047) mmol/L in the control group and 0.779 (±0.045) mmol/L in the study group. The serum Mg levels at 3, 6, 12, 24, 48 and 72 hours of life were 1.87 (±0.6), 1.65(±0.059), 1.468 (±0.91), 1.881 (±0.053), 1.916 (±0.053) and 1.493 (±0.084) mmol/L respectively in the study group. All these values were significantly higher than those obtained in the control group (p<0.001). No significant alterations in heart rate, respiratory rate, oxygen saturation and mean arterial pressure were seen, following magnesium infusion with either 250 mg/kg or 125 mg/kg dose. The serum Mg levels in the study group ranged between 1.493 (±0.084) and 1.916 (±0.053) mmol/L, which are considered to be in the neuroprotective range.Conclusion: Injection MgSO₄ administered in a dose of 250 mg/kg and 125 mg/kg as an intravenous infusion is safe, and the Mg levels obtained are in the range considered to be neuropropective.     

Methotrexate induces germ cell apoptosis and impairs spermatogenesis in a rat

Purpose

The primary toxic effects of methotrexate (MTX) are myelosuppression and/or intestinal mucositis. The objective of the present study is to investigate the effect of MTX on germ cell apoptosis and spermatogenesis in a rat.

Methods

Male Sprague–Dawley rats were divided into three experimental groups: control rats treated with vehicle; MTX-2 rats treated with one dose (20 μg/kg) of MTX given IP and killed on the second day; and MTX rats treated with IP MTX (20 μg/kg) and killed on day 4. Johnsen’s criteria and the number of germinal cell layers in the testes were used to categorize the spermatogenesis. TUNEL assay was used to determine germ cell apoptosis. Western blotting was used to determine Bax and Bcl-2 protein levels. Statistical analysis was performed using the non-parametric Kruskal–Wallis ANOVA test, with p less than 0.05 considered statistically significant.

Results

On day 2, MTX-treated animals demonstrated minimal changes in the histological parameters of spermatogenesis, but germ cell apoptosis increased significantly (threefold increase, p = 0.002) compared to control rats. On day 4, MTX-treated rats demonstrated a trend toward a decrease in germ cell apoptosis, compared to day 2, and showed histological signs of impaired spermatogenesis (decreased number of germ cell layers and Johnsen’s criteria). A significant increase in cell apoptosis in MTX-treated rats was correlated with higher Bax/Bcl-2 protein levels.

Conclusions

MTX induced germ cell apoptosis and impaired spermatogenesis in rat testes.     

法尼醇X受体在急性淤胆型肝炎大鼠模型中的表达及大黄素的干预作用

目的 研究核受体法尼醇X受体（FXR）在急性淤胆型肝炎大鼠模型中的表达及大黄素的干预作用。方法 将90只Sprague-Dawley成年大鼠随机分为正常对照组、模型组和大黄素干预组,每组30只。模型组和大黄素干预组给予α-异硫氰酸萘酯（ANIT）50 mg/kg一次灌胃,建立大鼠淤胆型肝炎动物模型,正常对照组给予等体积麻油进行替代;大黄素干预组分别于造模前连续4 d及造模后每日给予20 mg/kg大黄素灌胃,直至各组大鼠分别于造模后24、48、72 h处死,模型组和正常对照组给予等体积羧甲基纤维素钠溶液进行替代。实时荧光定量PCR法检测肝组织中FXR mRNA表达的变化;全自动生化分析仪检测血清总胆红素（TB）、直接胆红素（DB）、丙氨酸氨基转移酶（ALT）及胆汁酸（TBA）的水平。结果 造模后各时间点,模型组肝组织中FXR mRNA表达水平均低于正常对照组（均PPPP结论 大黄素可显著降低ANIT诱导的淤胆型肝炎大鼠血清中TB、DB、ALT、TBA水平,其作用机制可能与促进FXR表达有关。     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35–350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was < 4.5 × 10^?6 M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

Lipid peroxidation in bronchial asthma

Objective: To study the levels of free oxygen radicals in children with bronchial asthma during an attack and symptom free interval.Methods: Serum Malondiadehyde (MDA) levels were studied in 25 children between the age of 6 years-14 years who presented with an acute attack of bronchial asthma. In each patient, serum MDA levels were measured at the time of admission, 24–48 hours after good response to treatment and after a symptom free interval of 3 weeks. Results were compared with control group.Results: In study group serum MDA levels were highest at the time of admission, which decreased significantly at 24–48 hours with treatment. After a 3 weeks symptom free interval serum MDA levels had decreased further but were still higher than healthy control group.Conclusion: Lipid peroxidation is increased in bronchial asthma during an acute attack and symptom free period.     

肺表面活性物质对新生儿呼吸窘迫综合征患儿血清Th1/Th2平衡的影响

目的：探讨肺表面活性物质(PS)对新生儿呼吸窘迫综合征（NRDS）患儿血清Th1/Th2平衡和血清IgE浓度的影响。方法：纳入NRDS患儿共58名,其中未接受PS治疗、只给予机械通气和其他一般治疗的患儿 20例作为对照组;除机械通气及一般治疗外,入院1 h内应用牛肺表面活性剂治疗的患儿38例作为PS组。采用ELISA法检测两组患儿在治疗前及治疗后24、48、72 h血清中白细胞介素4（IL-4）、γ干扰素（IFN-γ）及IgE的浓度,同时记录动脉血气、呼吸系统顺应性等呼吸机参数。结果：PS组机械通气时间、氧暴露时间明显低于对照组（均P<0.05）。在治疗后24、48、72 h,PS组肺顺应性显著高于对照组,氧合指数显著低于对照组（P<0.05）。治疗后48和72 h,PS组IFN-γ血清浓度分别为120±46、141±40 ng/L,显著低于对照组（48和72 h分别为229±59、282±43 ng/L）;IL-4血清浓度分别为263±48、417±49 pg/mL,显著高于对照组（48和72 h分别为152±45、201±46 pg/mL）,差异均有统计学意义（P<0.05）。治疗后72 h,PS组血清IgE浓度（115±44 ng/mL）显著低于对照组（199±43 ng/mL）（P<0.05）。结论：PS不仅缩短机械通气和氧暴露时间,还可以调节血清IFN-γ、IL-4、IgE水平,影响Th1/Th2平衡,从而抑制肺部炎症反应,减轻肺损伤。     

Effects of oral zinc supplementation on zinc status and catch-up growth during the first 2 years of life in children with non-organic failure to thrive born preterm and at term

Background

We aimed to analyze the effect of oral zinc supplementation on serum insulin-like growth factor-1 (IGF-1) levels and catch-up growth in infants with non-organic failure to thrive (NOFTT) who were born preterm as compared to those born at term.

Compensatory hypertrophy and progressive renal damage in children nephrectomized for Wilms' tumor

Clinical, biochemical, and sonographic evaluation of the remaining kidney function and size was performed in 34 patients, 12 males and 22 females, ages 2.1–19.6 years, nephrectomized for Wilms' tumor at least 2 years before (mean 8.6). All patients had normal blood pressure and serum bicarbonates. Two of them had microhematuria, four proteinuria 4 mg/m2/hr, and 11 microalbuminuria (MA) >20 mg/24 hr. Only one patient had reduced creatinine clearance and maximum bipolar length (MBL) as well as kidney volume (KV) <100% of expected. In the other patients, average MBL was 128 ± 14% and KV was 213 ± 11% (P = 0.0001). MBL, but not KV, was inversely correlated (P = 0.04) to age at NP. KV, but not MBL, was directly correlated (P = 0.009) to MA. Average MA was 48 ± 94 mg/24 hr and was correlated to the time from NP (P = 0.026). The remaining kidney increases in volume much more than in length. The increase in KV is related to the degree of MA, whereas the increase in MBL is higher in subjects younger at NP. The high prevalence of significant MA, which is in turn related to the time from NP and to the KV, raises some concerns about the long-term renal prognosis of children NPWT. © 1996 Wiley-Liss, Inc.     

红花注射液对白血病HEL细胞增殖和凋亡的影响及相关机制探讨

目的 研究红花注射液对白血病HEL 细胞增殖、凋亡的影响,并初步探讨其相关分子机制。方法 HEL 细胞随机用或不用红花注射液处理,不用红花注射液处理者为对照组。不同浓度(10、20、30、40、50 mg/mL)的红花注射液作用于HEL 细胞24、48、72 h 后,采用四甲基偶氮唑蓝(MTT)法检测各组细胞增殖能力;10、20、30 mg/mL 红花注射液处理HEL 细胞48 h 后,采用流式细胞术检测各组细胞细胞周期与凋亡的变化,RT-PCR 法检测细胞HOXB3 mRNA 的表达。结果 HEL 细胞经浓度为10、20、30、40、50 mg/mL的红花注射液处理24、48 及72 h 后,与对照组比较,细胞增殖均不同程度地受抑制,且随着红花注射液浓度的增加,细胞增殖抑制率增加(PPPP结论 红花注射液体外可有效抑制HEL 细胞的增殖并诱导其凋亡,其相关分子机制可能与下调HOXB3基因的表达有关。     

Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high-dose methotrexate-citrovorum rescue

Three adolescents and one child with osteosarcoma were studied during multiple courses of high-dose methotrexate, citrovorum factor rescue (HDMTX-CFR), with one adolescent treated intermittently over a period of 6 years. Plasma phenylalanine (Phe) and tyrosine (Tyr) were measured immediately before the infusion of MTX and then daily until serum MTX fell below 10(-7) M. At 24 hours, all showed marked increases in Phe and in the Phe/Tyr ratio. This suggests inhibition of dihydropteridine reductase (DHPR) which, in association with hepatic Phe hydroxylase, controls plasma concentrations of Phe. Inhibition of this enzyme system is not relieved by CFR. In the adolescent patients, although MTX levels in plasma declined steadily, Phe concentrations, which fell between 24 and 48 hours, rose to a new peak at 4-7 days. Possible reasons for this secondary increase are discussed. The patient with the longest exposure to HDMTX showed an increase in pretreatment Phe/Tyr ratios with time, suggesting damage to liver parenchymal cells not indicated by standard tests of liver function. Evaluation of plasma Phe during the course of HDMTX-CFR may permit assessment of intracellular concentrations of MTX or its metabolites in the liver without interference by CFR.