Intermittent Blood Flow in Solid Tumours – an under-appreciated Source of ‘drug Resistance’

As the search for improved anti-cancer drugs continues, new paradigms concerning the reasons for clinical failures in common human solid tumours are also evolving. Classical drug resistance is now perhaps less often invoked to explain lack of treatment efficacy than are newer concepts, including contact resistance, tumour heterogeneity, regrowth resistance, and physiological barriers to drug delivery. This commentary will explore the resistance of solid tumours to chemotherapy from yet another, largely ignored perspective: that of tumour-specific fluctuations in blood flow. Transient decreases in blood flow have significant implications for delivery of chemotherapeutic agents, cellular responsiveness to those agents, and the regrowth potential of the surviving tumour cells.     

Drug and radiation resistance in spheroids: cell contact and kinetics

Cells from multicellular spheroids are often more resistant than monolayers to drugs and radiation. While explanations for resistance can be based on differences in cell cycle distribution, inability of the drug to penetrate the spheroid, or the presence of hypoxic cells, these mechanisms do not adequately explain resistance to all agents. Small spheroids (containing about 25–50 cells) exposed to ionizing radiation, hyperthermia, photodynamic therapy, or topoisomerase II inhibitors, are more resistant to killing than monolayers; the close three-dimensional contact in spheroids has been implicated in this resistance. Proposed mechanisms for the contact effect include gap junctional reciprocity, cell shape mediated changes in (repair-related) gene expression, and alterations in chromatin packaging which influence DNA repair. The consequences of the contact effect are especially important for multifraction exposures. Another form of resistance can be demonstrated during repetitive treatments; regrowth resistance reflects the capacity of spheroid cells to proliferate more efficiently to compensate for cell killing.     

Horizontal Maxillotomy for Exposure of the Central Skull Base: The Yale Experience

Le Fort I osteotomy allows the surgeon to safely down-fracture the maxilla for wide exposure of the central skull base. This surgical approach is easily extended inferiorly to include the arch of C1, providing 8cm of horizontal anterior exposure and 5cm of posterior. Wide operative exposure and a low rate of complications afford superior functional and cosmetic preservation in removing tumors of the central cranial base.     

Conjugation of interferon alpha to a humanized monoclonal antibody (HuBrE-3vl) enhances the selective localization and antitumor effects of interferon in breast cancer xenografts

Human mammary carcinoma xenografts (MCF-7) growing in nude mice were treated with natural interferon (n-IFN-) alone or conjugated to a humanized monoclonal antibody (MoAb) anti-breast mucin (HuBrE-3vl) or to irrelevant human IgG₁. The IFN and the conjugates were administered as 20 intra-lesional (i.l.) injections to 1 of 2 xenografts in each mouse, or i.p. The growth inhibitory effects of HuBrE-3vl/nIFN- were significantly greater than those of nIFN- used as a single agent or conjugated to HuIgG₁. These effects occurred locally in the tumors receiving i.l. injections and systemically, although to a slightly lesser extent, in the noninjected tumors of mice treated i.l. and in the xenografts of mice treated i.p. Biodistribution studies showed that the uptake of ¹²⁵I-HuBrE-3vl/nIFN- by the tumors 24 hours after i.l. or s.c. injection was greater than that of ¹²⁵I-HuIgG₁/nIFN-,¹²⁵ I-nIFN- alone, or by normal tissues, documenting a tumor targeting effect and favorable tumor:normal tissues (T:NT) ratios. The targeting effects and the resulting tumor growth inhibition were favored by the IFN-mediated up-regulation of the HuBrE-3vl reactive antigen, which was more prominent after 3 weeks of treatment with HuBrE-3vl/nIFN-. These results were superior to those we obtained previously with nIFN- conjugated to another MoAb of the same group (Mc5). These studies point out the potential usefulness of HuBrE-3vl/nIFN- for the local and systemic treatment of breast cancer lesions by providing a means of delivering high doses of IFN to the tumors while minimizing the amount of IFN binding to normal tissues.     

Shaping future strategies for the pharmacological control of tumor cell metastases

Summary The eradication of established metastases in patients with malignant tumors is the single most important objective in clinical oncology. The current panel of antineoplastic agents discovered through random and semiempirical screening procedures has proven largely ineffective in treating disseminated disease and there is a clear and urgent need for more efficient antimetastatic drugs. Unfortunately, although progress has been made in examining the biology of metastatic spread, our understanding of the pharmacology, biochemistry and molecular genetics of this process is meager and insufficient to provide a rational foundation for the design of mechanism-based antineoplastic agents. Faced on the one hand with the failure of existing drugs to control metastatic spread and on the other with a dearth of alternative pharmacological approaches, the prospect of offering significantly improved therapy to the cancer patient of the 1990's is poor. The challenge of the coming decade lies in obtaining better insights into the molecular mechanisms of metastasis and using this information to identify pharmacological opportunities to curtail the proliferation of secondary tumor growths. As a first step toward this goal we need to define more rigorously what constitutes a therapeutic target in malignant disease and what steps in the pathogenesis of cancer metastasis represent the gravest risk to the patient and thus are most eligible for direct pharmacological intervention. In addressing these issues and developing future strategies for antimetastatic drugs, Paget's 100 year-old seed and soil hypothesis continues to offer a useful conceptual framework for analysis of metastatic behavior. Although Paget's proposal has been validated by a century of clinical observation, efforts to define the seed and soil theory in molecular terms have not been attempted. With the advent of more efficient methodologies for culturing human normal and neoplastic cells coupled with the availability of microanalytical technologies it now becomes possible to investigate and identify the complementary biochemical components of the tumor cell seed and organ soil that combine to encourage the proliferation of metastases. With this information the design of specific pharmacological strategies to uncouple the seed and soil relationship may emerge as a potential therapeutic approach for antagonizing the growth of disseminated malignant tumors.     

Pediatric Medulloblastoma: Prognostic Value of p53, bcl-2, Mib-1, and Microvessel Density

The aim of this study was to retrospectively assess the prognostic value of p53 and bcl-2 protein expression, cell proliferation index (Mib-1 index), and tumor microvessel density (factor VIII-related antigen) in pediatric medulloblastoma patients. Tumor specimens of 55 patients (age 2–18 years) with medulloblastoma treated with a curative intent between 1972 and 1991 were studied. Slides of paraffin embedded tissue were stained with monoclonal antibodies (mAb) and examined under high power light microscopy for the presence of immunoreactivity. Microvessel density was scored both in the area of most intense staining (Angio-max) and in 3 additional randomly selected areas. The sum of these 4 scores was termed Angio-total. Angio-max and Angio-total were evaluated separately by two independent investigators to assess reproducibility. None of the parameters studied, i.e. p53 or bcl-2 expression, Mib-1 index or microvessel density scores were associated with patient survival. Microvessel scores between observers were significantly but weakly correlated, with correlation coefficients (r)<0.5 for both Angio-max and Angio-total. Leptomeningeal spread at diagnosis was the only independent factor associated with a poor survival (p=0.003). There was no association of leptomeningeal metastasis with any of the biological markers tested in this study.     

Up-regulation of γ-glutamylcysteine synthetase activity in melphalan-resistant human multiple myeloma cells expressing increased glutathione levels

Levels of intracellular glutathione (GSH) and the GSH-related enzymes -glutamylcysteine synthetase (-GCS) and -glutamyltranspeptidase (-GT) were measured in the melphalan-resistant human multiple myeloma cell line 8226/LR-5 and were compared to those measured in the drug-sensitive 8226/S and doxorubicin-resistant 8226/Dox40 cell lines. Both GSH and -GCS activity, the rate-limiting step in the de novo synthesis of GSH, were elevated by a factor of approximately 2 in the melphalanresistant 8226/LR-5 cells relative to the other two lines. -GT activity was not elevated significantly in the /LR-5 cells. Northern analysis with a probe specific for the large subunit of human liver -GCS identified two bands (3.2 and 4.0 kb), both of which were increased by a factor of 2–3 in the 8226/LR-5 line. Levels of -GCS mRNA expression were comparable in the /S and /Dox40 cell lines. Levels of -GT mRNA were similar in the /S and /LR-5 lines but were reduced in the /Dox40 cells. These data suggest that the increased GSH levels associated with resistance to melphalan in the 8226/LR-5 myeloma cells is attributable to up-regulation of -GCS. This observation is consistent with recent demonstrations of up-regulation of -GCS in melphalan-resistant prostate carcinoma cells and cisplatinum-resistant ovarian carcinoma cells, suggesting that increased expression of -GCS may be an important mediator of GSH-associated resistance mechanisms.     

Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine

The present study shows that various cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interferon- (IFN) make tumor cells much more susceptible to the cytostatic 5-deoxy-5-fluorouridine (5-dFUrd) than to 5-fluorouracil (5-FUra) and other cytostaties. These three cytokines increased the susceptibility of human cancer cell lines (COLO201, MKN45 and WiDr) but did not affect that of normal fibroblast WI38 cells. The cytokine mixture induced a 50-fold increase in the susceptibility of COLO201 to 5-dFUrd, whereas a 12-fold increase and a less than 5-fold enhancement in the susceptibility to 5-FUra and other cytostatics, respectively, were observed. The increased susceptibility would be a result of the induction of thymidine phosphorylase (TdR Pase), which is the essential enzyme for the conversion of 5-dFUrd to 5-FUra. The cytokine mixture increased TdR Pase activity by up to 47 times and greatly induced its mRNA expression in the cancer cell lines. These results suggest that the therapeutic benefit of 5-dFUrd would be improved by its use in combination with the cytokines.     

Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4′-O-methyldoxorubicin in tumor-bearing mice

Summary It has been reported that 4-demethoxy-4-O-methyldoxorubicin (4-dm-4-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%–50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%–3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4-O-methylDX, as a percentage of the administered dose, was 1.3–2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.The work described in this paper was supported by grant N. 84.00855.44 of the Oncologia project of the Consiglio Nazionale delle Ricerche, Rome, Italy     

Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain

We examined a possible role for the adhesion molecules LFA-1 and ICAM-1 in localizing central nervous system non-Hodgkin's lymphomas (CNS-NHLs) to the brain. Fresh frozen sections from 12 monoclonal CNS NHLs (11 primary, one secondary) were stained with monoclonal antibodies to LFA-1 chain (CD11a), chain (CD18) and, ICAM-1 (CD54). Additional staining made use of rat monoclonal antibodies to the human and mouse high endothelial venule antigens HECA 452 and MECA 79 and mouse ICAM-1. The expression of these same molecules was also studied in mice with severe combined immunodeficiency (SCID) mice, bearing intracranial human lymphoblastoid cells.Eleven of the CNS-NHL tumors expressed LFA-1 (one strongly, one intermediate, nine weakly). Nine of the tumors weakly expressed LFA-1.. Nine of twelve tumors weakly expressed ICAM-1. In six of seven tumors definite blood vessels stained for ICAM-l. Non-tumor brain from two patients and non-tumor cerebral blood vessels showed no staining with CD11a, CD18 or CD54 antibodies. Strong expression of LFA- and LFA- as well as ICAM-1 was noted in human lymphoblastoid cells (LCLs)/SCID mouse CNS lymphomas. Tumor blood vessels in these mice stained for mouse ICAM-1. Normal SCID mouse brains showed no staining with CDII, CD18, CD54 or mouse ICAM-1 antibodies. Human, human/mouse CNS lymphomas, normal human, and mouse brains showed no staining with either HECA 452 or MECA 79.Our data suggests that CNS lymphomas express LFA-1, LFA-1 and to a lesser degree ICAM-1 antigen, while tumor blood vessel endothelium expresses ICAM-1. LFA-1-LFA-1/ICAM-1 interaction may play a role in large cell lymphoma homing and persistence in the brain.     

Metastatic Spinal Cord Compression In Patients With Colorectal Cancer

Reduced blood cholesterol levels were reported in patients with a variety of malignant peripheral tumors. This fact is likely related to increased cholesterol demand by proliferating tumor cells. The question arises whether this tumor-associated hypocholesterolemia occurs also in patients with brain tumors, and – if it does not – whether its absence can be related to the location of the tumors. We have compared fasting serum total cholesterol levels among three groups of patients: 52 patients with gliomas, 56 patients with symptomatic metastatic brain tumors, and 50 patients harboring malignant tumors of peripheral location but showing no clinical signs of brain metastases. Patients in the last group, despite being – on an average – more age-advanced, had lower total serum cholesterol levels than either the patients with gliomas, or the patients with brain metastases. No difference in the cholesterol levels was found between the two latter groups, and a majority of these patients had borderline or elevated cholesterol levels. This apparent absence of tumor-associated hypocholesterolemia in brain tumor patients may be related to either brain tumors' ability to synthesize cholesterol de novo and their reduced dependence on peripheral cholesterol supply, the existence of brain tumor–blood barrier, effect of medications used to counteract brain edema and seizures, or a combination of these factors.     

New approach to metabolism of 5′-deoxy-5-fluorouridine in humans with fluorine-19 NMR

Summary The metabolism of 5-deoxy-5-fluorouridine (5dFUrd), an antitumor fluoropyrimidine, has been investigated in human biofluids (blood, plasma, urine) using a new method: fluorine-19 NMR spectrometry. This method allows direct study of the biological sample and simultaneous identification of all the fluorinated metabolites. In the blood of a patient treated with 5dFUrd during a 6-h continuous perfusion, we observed unmetabolized 5dFUrd, 5-fluorouracil, 5,6-dihydrofluorouracil, and another metabolite which has not previously been reported -fluoro--alanine. The two major metabolites in urine are unmetabolized 5dFUrd and -fluoro-alanine.     

In vivo effects in mice produced by a 3′-branched homologue of α-2′-deoxythioguanosine

Summary Studies with a 3-branched chain homolog (-3-BCTGdR) of 2-deoxythioguanosine (-TGdR) showed that it did not prolong the survival of mice bearing the Mecca lymphosarcoma. Host toxicity was quite profound and resembled that seen with 6-thioguanine (6-TG). Evidence was obtained that this nucleoside derivative was not appreciably converted to 6-TG in the mouse. Mice treated with toxic doses of 6-TG or -3-BCTGdR were found to have very similar pathological changes. The granulocytes were eliminated from the peripheral blood, bone marrow was acellular, and some more limited damage was seen in the intestinal crypts. Experiments with radiosulfur-labeled drugs demonstrated that -3-BCTGdR was incorporated into the DNA of mouse bone marrow, predominantly in the chain-terminating position, with the result that shorter chains of DNA accumulated. The new homolog, unlike -TGdR, was phosphorylated in bone marrow as well as in tumor, and incorporated well into the DNA both of bone marrow and of the neoplastic cells. In devising other homologs attention must be given to the specificity of the kinases, i.e., to whether phosphorylation is superior in tumor cells or in the growing normal cells.Abbreviations used are 6-TG 6-thioguanine - ,-TGdR ,-2-deoxythioguanosine - -3-BCTGdR 6-thioguanine--2,3-dideoxy-3-(hydroxymethyl)-d-erythro-pentofuranose - ³H-TdR Tritium-labeled (methyl) thymidine     

Effects of scheduling and ascites-associated macrophages on combined antiproliferative activity of alpha-2b interferon and gamma-interferon in a clonogenic assay

Summary Effects of combination treatment with human recombinant alpha-2b interferon (IFN-2b) and gamma interferon (IFN-) and sequencing of the combination on colony formation of human tumor cells were studied in a human tumor clonogenic assay (HTCA) with or without ascites-associated macrophages (AAM). Five different human tumor cell lines were studied. Three of the five cell lines (ovarian cancer cell line BG-1, cervical cancer cell line ME-180, and melanoma cell line SK-MEL 28) were sensitive to both IFNs.Cervical cancer cell line CaSki was sensitive to IFN-2b but resistant to IFN-. Endometrial cancer cell line HEC-1A was resistant to both IFNs. Synergistic interaction was observed in BG-1 and SK-MEL 28 with a combination of the IFNs. ME-180 did not exhibit a positive interaction, in spite of its sensitivity to each IFN. CaSki and HEC-1A also did not exhibit a positive combined interaction at clinically achievable concentrations. One sequential combination method (method 1: IFN-2b IFN gamma with a 24-h interval) resulted in a similar antitumor effect as the simultaneous combination. A reversed sequential method (method 2: IFN- IFN-2b with a 24-h interval) was less effective in three of the five cell lines. In BG-1, AAM enclosed in the lower layer markedly enhanced the antitumor effect of combined IFNs as well as each IFN alone. The antitumor effect with method 1 was significantly greater than that achieved with simultaneous combination or combination according to method 2 in the presence of AAM (P<0.01). These results suggest that (1) a synergistic antitumor effect of IFN-2b and IFN gamma is demonstrable in selected types of tumors, depending upon the sensitivity of each tumor cell line to both IFNs; (2) optimal scheduling for the direct antitumor effect of combined IFNs seems to be long-term exposure of cells to the IFN, the cells being treated with both IFNs either simultaneously or sequentially (IFN-2b preceding IFN-); and (3) AAM potentiate the antitumor effect of IFNs either alone or in combination. Finally, IFN-2b may have some priming effects for the indirect effect of IFN gamma mediated through AAM in certain tumor cells.     

START: A European state-of-the-art on-line instrument for clinical oncologists

START (State-of-the-Art Oncology in Europe), a freely available resource on the Internet, is a European information base of current clinical approaches to human tumours. Its aim is to help clinical oncologists make appropriate clinical decisions by providing them with updated information reflecting state-of-the-art cancer treatment as perceived by the European oncology community. It is based upon contributions from authors and internal reviewers from all over Europe as selected by START's editorial board under the supervision of an advisory board and a scientific committee. Close collaborations with the main European cancer societies are ongoing. An external feedback process augments the mechanisms for rendering START a truly European instrument. START is concerned with evidence-based cancer medicine, and the main clinical options are thus codified and their bases indicated in accord with a scale worked out from the perspective of clinical decision-making. Therapeutic options may be standard, investigational, or suitable for individual clinical use (within the context of a decision made jointly by the patient and the physician). The goal of instruments such as START is to improve the quality of patient care. In addition, START hopes to make contributions to the methodology by which medical research is transformed into clinical decisions.     

Glycogen‐rich carcinomas of the breast display unique characteristics with respect to proliferation and the frequency of oligonucleosomal fragments

We determined the proliferation rate and apoptotic activity of glycogenrich carcinomas of the breast as opposed to nonclear cell tumors by means of MIB1 immunohistochemistry and in situ detection of oligonucleosomal fragments (TUNEL reaction). The retrospective biopsy series included six invasive clear cell carcinomas of the glycogenrich type as well as 15 randomly selected cases of invasive ductal carcinoma without evidence of glycogen storage. Three patients in the clear cell group and seven patients in the control cohort developed lymphnode metastasis. The MIB1 labeling index of glycogenrich carcinomas averaged 9.05%, while that of the controls was 30.03%. Apoptotic nuclei were present in a mean of 1.26% of glycogenrich carcinoma cells. The control tumors exhibited an average apoptotic frequency of 5.85%. Tumor size, hormone receptor status, and presence or absence of lymph node involvement were found not to correlate with either proliferation or apoptosis. We conclude that glycogenrich breast carcinomas are characterized by a peculiar low proliferationlow apoptosis cell kinetic profile. The aggressive clinical behavior of these neoplasms may possibly be accounted for by an ineffective apoptotic elimination of otherwise slowly proliferating tumor cells.     

Impact de l’accès à Internet dans la relation médecin/malade en cancérologie. Réflexions à partir d’un cas clinique.

Résumé: De plus en plus de patients atteints de cancer surfent sur Internet pour trouver des informations sur leur pathologie. Les caractéristques dInternet—facilité daccès, absence de médiation, encyclopédisme, profusion—bouleversent les modes daccès, de transmission et dutilisation du savoir médical. La relation médecin/patient en est bouleversée, plus spécialement dans le cas des maladies graves où le contenu émotif lié à la délivrance du diagnostic (et plus encore du pronostic) exacerbe les enjeux de la relation. À partir dun cas clinique particulièrement représentatif, cet article a pour objet de réfléchir à différentes problématiques:—quen est-il de linformation médicale aujourdhui?—lutilisation dInternet est-elle susceptible dentraver ladaptation psychique des patients confrontés au cancer?—quelles réflexions peut-on en tirer pour la pratique du cancérologue?     

Influence of tumor size on the main drug-metabolizing enzyme systems in mouse colon adenocarcinoma Co38

Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917±444 mg (range, 300–1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8–10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-,-, and-) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), -glucuronidase (G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P<0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-, GST-, GSH, and G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P<0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Association pour la Recherche sur le Cancer (ARC, Villejuif)     

Pharmacokinetics of carboplatin administered with lobradimil to pediatric patients with brain tumors

Purpose To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors.Methods Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mgmin/ml per dose ×2 (2.5 mgmin/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m²)=target AUC (mgmin/ml) × [0.93 × GFR (ml/min/m²)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity.Results The median GFR was 65 ml/min/m² (range 38–95 ml/min/m²) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m²/day (124–235 and 179–360 mg/m²/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mgmin/ml target AUCs were 3.4 and 4.8 mgmin/ml (2.51–5.8 and 3.9–7.7 mgmin/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r²=0.14).Conclusions Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.