Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts

Purpose To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo. Methods H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2014-11, Vol.74 (5), p.1029-1032
Main Authors: Tedeschi, Philip M., Kathari, Yamini K., Farooqi, Iqra N., Bertino, Joseph R.
Format: Article
Language:English
Subjects:
Aminopterin - administration & dosage
Aminopterin - analogs & derivatives
Aminopterin - pharmacology
Animals
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Body Weight - drug effects
Cancer Research
Cell Line, Tumor
Cell Survival - drug effects
Dose-Response Relationship, Drug
Drug Synergism
Female
Folic Acid Antagonists - administration & dosage
Folic Acid Antagonists - pharmacology
Glutamates - pharmacology
Guanine - analogs & derivatives
Guanine - pharmacology
Humans
Leucovorin - administration & dosage
Leucovorin - pharmacology
Medical sciences
Medicine
Medicine & Public Health
Mesothelioma - drug therapy
Mesothelioma - pathology
Methotrexate - pharmacology
Mice, Nude
Oncology
Original
Original Article
Pemetrexed
Pharmacology. Drug treatments
Pharmacology/Toxicology
Time Factors
Tumor Burden - drug effects
Vitamin B Complex - administration & dosage
Vitamin B Complex - pharmacology
Xenograft Model Antitumor Assays
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Summary:Purpose To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo. Methods H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV. Results In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression. Conclusions High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-014-2580-z