Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines

We previously found that low shear stress (LSS) induces atherosclerotic plaques in mice with increased lipid and matrix metalloproteinase content and decreased vascular smooth muscle and collagen content. Here, we evaluated the role of chemokines in this process, using an extravascular device inducing regions of LSS, high shear stress, and oscillatory shear stress (OSS) in the carotid artery. One week of shear stress alterations induced expression of IFN-gamma-inducible protein-10 (IP-10) exclusively in the LSS region, whereas monocyte chemoattractant protein-1 (MCP-1) and the mouse homolog of growth-regulated oncogene alpha (GRO-alpha) were equally upregulated in both LSS and OSS regions. After 3 weeks, GRO-alpha and IP-10 were specifically upregulated in LSS regions. After 9 weeks, lesions with thinner fibrous caps and larger necrotic cores were found in the LSS region compared with the OSS region. Equal levels of MCP-1 expression were observed in both regions, while expression of fractalkine was found in the LSS region only. Blockage of fractalkine inhibited plaque growth and resulted in striking differences in plaque composition in the LSS region. We conclude that LSS or OSS triggers expression of chemokines involved in atherogenesis. Fractalkine upregulation is critically important for the composition of LSS-induced atherosclerotic lesions.     

Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression

Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2-/- cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2-/- cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.     

Hepatic drug clearance in children with leukemia: changes in clearance of model substrates during remission-induction therapy

We administered a "cocktail" of three model substrates for hepatic processes: antipyrine for oxidation, lorazepam for glucuronidation, and indocyanine green for hepatic blood flow, to children with acute lymphocytic leukemia (ALL). The plasma clearance of these substrates was determined before and after remission-induction therapy in 14 children with ALL. We found an improvement in clearance of antipyrine (0.65 to 0.95 ml/min/kg; P less than 0.01) and lorazepam (0.93 to 1.20 ml/min/kg; P less than 0.05) in 12 of 14 patients, with a mean increase of 67% and 52%, respectively, from before to after remission. There was no significant difference in mean indocyanine green clearance from before to after induction (14.8 vs. 14.4 ml/min/kg). There were no significant differences in liver function test results (SGOT, prothrombin time, or serum bilirubin) from before to after induction. Plasma concentrations of albumin, alpha 1-acid glycoprotein, and apolipoprotein A changed by a mean of +11.1%, -38.2%, and +68.6%, respectively, from before to after remission. However, these changes did not account for the changes in total plasma clearance of lorazepam, because lorazepam free fraction did not change and lorazepam free clearance increased by a mean of 83%. Our hypothesis is that eradication of hepatic leukemic infiltration by ALL remission therapy resulted in an improvement in microsomal metabolism of antipyrine and lorazepam.     

Topoisomerase I interactive drugs in children with cancer

Topotecan, irinotecan, and 9-aminocamptothecin (9-AC) are analogs of the plant alkaloid 20(S)-camptothecin (CMT), the prototypical DNA topoisomerase I interactive agent. These agents interact with the topoisomerase I-DNA complex and prevent resealing topoisomerase I-mediated DNA single-strand breaks. This eventual leads to double-strand DNA breaks and apoptosis or cell death. Topotecan, irinotecan, and 9-AC have shown significant activity in mice bearing pediatric solid tumor xenografts; the greatest antitumor responses were found with protracted continuous schedules. Preclinical data also suggest that maintenance of an exposure-duration threshold (EDT) may be required to achieve optimal cytotoxicity. Pediatric Phase I trials have evaluated the toxicity and safety of camptothecin analogs in children with relapsed solid tumors and relapsed acute leukemia. The primary dose-limiting toxicity (DLT) for the CMT analogs in children has been myelosuppression, except for mucositis observed with the 120-hr continuous topotecan infusion schedule. Pharmacodynamic relationships with these analogs have been reported between systemic exposure, and myelosuppression and mucositis. Although not a primary objective of the early Phase I studies, antitumor responses have been reported. In this review, the pharmacokinetics and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed. Address for offprints: Clinton F. Stewart, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA     

Workplace experiences and turnover intention among adult survivors of childhood cancer

Purpose

The purpose of this study was to investigate workplace experiences and turnover intention (consideration of leaving or changing a job) and to examine factors associated with turnover intention among survivors.

Methods

Adult survivors of childhood cancer with a history of employment (n?=?289) completed measures of workplace experiences (n?=?50, 18–29 years; n?=?183, 30–44 years; n?=?56; >?45 years of age at follow-up). Turnover intention was assessed using three items from the Job Satisfaction Scale. Responses were dichotomized as reflecting high vs. low turnover intention. Path analysis was used to estimate the influence of demographic characteristics, treatment exposures (cranial radiation therapy [CRT]), and workplace experiences on turnover intention.

Results

Thirty percent of survivors reported high turnover intention (95% CL, 25 to 36%). Exposure to CRT (P?=?0.003), older attained age (P?<?0.001), experiencing formal workplace discrimination (P?=?0.008), and having lower continuance (P?<?0.001) or affective commitment (P?<?0.001) were associated with high turnover intention among survivors. Informal discrimination, mediated through job satisfaction, also influenced survivors’ reported intent to leave their jobs.

Conclusions

One third of adult survivors of childhood cancer report turnover intention, which is related to their cancer treatment, but more temporally proximal, workplace discrimination. Additional research is needed to understand the consequences of turnover intention among survivors.

Implications for Cancer Survivors

Survivors and their health care providers should be aware of legislative policies related to workplace discrimination (e.g., American with Disabilities Act) and related implications for job turnover.

     

Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children

The feasibility and reliability of simultaneously determining debrisoquin oxidation and N-acetylation phenotypes was assessed in children with use of two innocuous substrate probes given by mouth, 30 mg dextromethorphan (Pertussin ES) and 25 to 46 mg caffeine (Coca-Cola beverage). Twenty-six children and adolescents (aged 3 to 21 years) were studied three times, once with each substrate given alone and once with the two substrates given together. Urine was collected for 4 hours, and the molar urinary metabolic ratios for dextromethorphan:dextrorphan and for two caffeine metabolites (AFMU:1X) were determined by HPLC ultraviolet assays. The urinary metabolic ratios for both substrates were not significantly different when the substrates were given alone compared with when they were given together. There also was no difference in either the oxidation or acetylation phenotype assignments when the two substrates were given alone and when they were given together. No adverse effects were observed. We conclude that dextromethorphan and caffeine can be given together to simultaneously determine oxidation and acetylation phenotypes and can thereby provide an innocuous, noninvasive method for the assessment of polymorphic drug metabolism in various pediatric populations.     

Bleomycin disposition in children with cancer

Bleomycin kinetics were determined in 14 children after intravenous bolus and prolonged infusion doses. Plasma and urine bleomycin concentrations were determined by radioimmunoassay. After intravenous bolus, bleomycin concentrations were adequately described by a two-compartment open model with a mean t1/2 alpha and t1/2 beta of 0.3 +/- 0.1 and 3.2 +/- 0.7 hr (mean +/- SEM). Volume of the central compartment and volume of distribution at steady-state (Vss) were 4.3 +/- 0.5 and 9.9 +/- 1.1 l/m2. Total plasma (CLT) and renal (CLR) clearance were 51.8 +/- 6.1 and 33.5 +/- 2.4 ml/min/m2. Three intravenous bolus courses were given to two patients who received more than four courses of cisplatin (greater than 300 mg/m2); CLT and CLR for these courses were 18.0 +/- 3.3 and 8.2 ml/min/m2. Conversely, children under 3 yr old eliminated bleomycin more rapidly than older children. Decline in bleomycin concentrations after seven 24- or 48-hr intravenous infusions was described by a one-compartment model. Mean values for plasma t1/2, Vss, CLT, and CLR were 2.1 +/- 0.1 hr, 11.0 +/- 2.6 l/m2, 57.1 +/- 13.5 ml/min/m2, and 33.2 +/- 6.4 ml/min/m2. One patient received his bleomycin infusion when ureteral obstruction was present; CLT and CLR for this course were 4.8 and 4.1 ml/min/m2. These data indicate that young children eliminate bleomycin more rapidly than older children and that children with impaired renal function may have prolonged elevations in plasma concentration due to reduced bleomycin clearance. Bleomycin disposition in older children is as in adults.