Influence of schedule of administration on methotrexate penetration in brain tumours

Dukic, Sylvain; Heurtaux, Tony; Kaltenbach, Matthieu L.; Hoizey, Guillaume; Lallemand, A; Vistelle, Richard

doi:10.1016/s0959-8049(00)00142-8

Cited by 24 publications

(14 citation statements)

References 16 publications

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“…6 However, the HDMTX infusion time of 24 hours might have been suboptimal, according to more recent findings concerning the use of methotrexate in PCNSL. 21,22 Similar results have been reported in other multicenter analyses with a median OAS of 9 months and 17 months, respectively. 2,3 This is most likely because of a relatively small proportion of patients treated with HDMTX (at a dose of >1 g/m 2 ) in these trials and supports our previous conclusion that PCNSL patients should preferably be managed at highly experienced centers.…”

Section: Discussionsupporting

confidence: 86%

Primary central nervous system lymphoma

Kiewe¹,

Fischer²,

Martus³

et al. 2008

Cancer

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BACKGROUND.This retrospective, single‐center study assessed the feasibility, outcome, and late side effects of the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL) at the authors' institution.METHODS.All 72 consecutive patients diagnosed with PCNSL between January 1994 and February 2005 were scheduled to receive high‐dose methotrexate (HDMTX)‐based chemotherapy.RESULTS.The median age of the patients was 62 years and the median Karnofsky performance score (KPS) was 70. Twelve patients did not receive HDMTX‐based chemotherapy because of poor physical condition or renal insufficiency. Of the 60 patients treated with HDMTX‐based chemotherapy, the treatment of 9 was followed with whole‐brain irradiation. Of 54 patients who were evaluable for response, 35 (65%) responded (52% with a complete response and 13% with a partial response), and 19 patients (35%) did not. At a median follow‐up of 58.7 months, the median progression‐free survival was 9 months and the median overall survival (OAS) was 41.4 months. According to the Memorial Sloan‐Kettering Cancer Center (MSKCC) prognosis score, patients could be divided into 3 groups with significantly different OAS: 52.9 months for patients aged <50 years, 42.4 months for patients aged ≥50 years and with a KPS >70, and 5.2 months for patients aged ≥50 years and with a KPS <70 (P = .009, log‐rank test).CONCLUSIONS.Promising long‐term results could be achieved with HDMTX‐based chemotherapy in patients with PCNSL in this monocenter study. The MSKCC score proved useful for predicting survival. Cancer 2008; 112:1812–20. © 2008 American Cancer Society.

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Section: Discussionsupporting

confidence: 86%

Primary central nervous system lymphoma

Kiewe¹,

Fischer²,

Martus³

et al. 2008

Cancer

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“…Human PCNSL show variable sensitivity to methotrexate-based chemotherapies with a complete remission rates ranging from 30% to 50% in various studies after multiple courses of chemotherapy (23 -26). Many factors could be responsible for the lack of methotrexate response in our pilot in vivo study, including the pharmacology of methotrexate or leucovorin rescue (27,28) or the short time frame of the pilot study. Delivery of agents across the BBB and brain-tumor barrier is a major issue limiting the efficacy of chemotherapeutic approaches to brain tumor therapy (9,12).…”

Section: Discussionmentioning

confidence: 99%

Characterization and Magnetic Resonance Imaging of a Rat Model of Human B-Cell Central Nervous System Lymphoma

Soussain

Muldoon²,

Várallyay

et al. 2007

Clinical Cancer Research

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Purpose: The incidence of primary central nervous system lymphoma (PCNSL) is increasing.Therapeutic approaches remain controversial. An animal model that mimics the clinical situation would be useful for evaluating PCNSL biology and treatment. Experimental Design: Nude rats received intracerebral (caudate nucleus, n = 49) or intraventricular (n = 4) inoculation of human B-lymphoma cell line MC116. Two to five weeks after tumor inoculation, magnetic resonance imaging (MRI) was done (n = 24), and rat brains were assessed for pathology. Five rats each received whole-brain radiotherapy (WBRT, 20 Gy) or high-dose i.v. methotrexate (3 g/m 2 ). Results: Intracerebral tumors developed in 84% of evaluable animals with no pretreatment, 79% of rats pretreated with 4 Gy total body irradiation, and 92% of rats pretreated with cyclophosphamide (300 mg/m 2 ). MRI showed abnormal T2 signal and gadolinium enhancement on T1-weighted images, consistent with tumor growth 19 to 24 days after inoculation. Tumor cells staining positively for B-lymphoma markers infiltrated within the inoculated hemisphere, along fiber tracks to the contralateral hemisphere, and along the subarachnoid space and ventricles. Tumors showed reactive gliosis. Intraventricular tumor cell injection resulted in periventricular parenchymal infiltration in both hemispheres. Radiation and methotrexate were effective in vitro, but only WBRT was clearly effective after 1 week in the intracerebral model. Conclusion: This model closely mimics human PCNSL in terms of imaging, histology, and treatment sensitivity and will be useful for the development of future therapeutic strategies for PCNSL.

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“…This may be partly due to the fact that pemetrexed is more lipophilic than that of MTX (data not shown). Previous microdialysis studies have shown that the ratio of unbound MTX level in brain versus the total MTX level in plasma ranges from 0.01 to 0.02 in terms of the AUC ECF,unbound /AUC plasma,total when it was administered by intravenous bolus dose (Devineni et al, 1996;Dukic et al, 1999Dukic et al, , 2000. In our intravenous bolus study, the AUC ECF,unbound /AUC plasma,unbound is 0.078, which would give a ratio of AUC ECF,unbound /AUC plasma,total of approximately 0.05, given the free fraction of pemetrexed in rat plasma of 0.36 (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Distribution of the Novel Antifolate Pemetrexed to the Brain

Dai¹,

Chen

Elmquist

2005

The Journal of Pharmacology and Experimental Therapeutics

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Pemetrexed disodium is a novel antifolate that exhibits potent inhibitory effects on multiple enzymes in folate metabolism. Phase II/III clinical trials have shown that pemetrexed is effective against various solid tumors. Like methotrexate, pemetrexed may be useful in treatment of primary and secondary brain tumors. In this study, we examined the central nervous system (CNS) distribution of pemetrexed and the interaction with an organic anion transport inhibitor indomethacin. Male Wistar rats were administered pemetrexed by either single intravenous bolus or constant intravenous infusion. Unbound pemetrexed in blood and brain was measured by simultaneous arterial blood and frontal cortex microdialysis sampling. In the i.v. bolus experiments, indomethacin was administered by i.v. bolus (10 mg/kg) followed by i.v. infusion (0.1 mg/kg/h) in a crossover manner. In the infusion experiments, the same dose of indomethacin was administered after a steady state was reached for pemetrexed. CNS distributional kinetics was analyzed by compartmental and noncompartmental methods. Both bolus and infusion studies showed that pemetrexed has a limited CNS distribution. The mean area under concentrationtime curve (AUC) brain /AUC plasma ratio of unbound pemetrexed was 0.078 Ϯ 0.038 in the i.v. bolus study. The pemetrexed steady-state brain-to-plasma unbound concentration ratio after i.v. infusion was 0.106 Ϯ 0.054. The distributional clearance into the brain was approximately 10% of the clearance out of the brain in both the compartmental and noncompartmental analyses. Indomethacin had no effect on either the brain-toplasma AUC ratio or the steady-state brain-to-plasma concentration ratio. The distribution of pemetrexed into the brain is limited, and an efflux clearance process, such as an efflux transporter, may be involved.

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Influence of schedule of administration on methotrexate penetration in brain tumours

Cited by 24 publications

References 16 publications

Primary central nervous system lymphoma

Primary central nervous system lymphoma

Characterization and Magnetic Resonance Imaging of a Rat Model of Human B-Cell Central Nervous System Lymphoma

Distribution of the Novel Antifolate Pemetrexed to the Brain

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