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

Tedeschi PM, Kathari YK, Farooqi IN, Bertino JR - Cancer Chemother. Pharmacol. (2014)

Bottom Line: 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.High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, USA.

ABSTRACT

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.

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Related in: MedlinePlus

A and B Pralatrexate is effective against H2052 xenografts. Mice bearing 100 mm3 tumors were treated by i.p injection of saline control; 60 or 180 mg/kg PDX on days 1, 4 and 7; 60 or 180 mg/kg PDX on days 1, 4 and 7 followed by 50 mg/kg leucovorin 24, 32 and 48 h after each PDX administration; 50 mg/kg leucovorin. Tumor volume (a) and body weight (b) were measured
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Fig3: A and B Pralatrexate is effective against H2052 xenografts. Mice bearing 100 mm3 tumors were treated by i.p injection of saline control; 60 or 180 mg/kg PDX on days 1, 4 and 7; 60 or 180 mg/kg PDX on days 1, 4 and 7 followed by 50 mg/kg leucovorin 24, 32 and 48 h after each PDX administration; 50 mg/kg leucovorin. Tumor volume (a) and body weight (b) were measured

Mentions: The effect of LV treatment on PDX efficacy and toxicity was examined using H2052 xenografts in nude mice (Fig. 3). Using 60 mg/kg as the equivalent clinical dose, tumor regression was seen both with and without LV treatment in this cohort. Efficacy was nearly identical, but mice that were treated with LV had less toxicity and bodyweight remained close to control animals.Fig. 3


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

Tedeschi PM, Kathari YK, Farooqi IN, Bertino JR - Cancer Chemother. Pharmacol. (2014)

A and B Pralatrexate is effective against H2052 xenografts. Mice bearing 100 mm3 tumors were treated by i.p injection of saline control; 60 or 180 mg/kg PDX on days 1, 4 and 7; 60 or 180 mg/kg PDX on days 1, 4 and 7 followed by 50 mg/kg leucovorin 24, 32 and 48 h after each PDX administration; 50 mg/kg leucovorin. Tumor volume (a) and body weight (b) were measured
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4209237&req=5

Fig3: A and B Pralatrexate is effective against H2052 xenografts. Mice bearing 100 mm3 tumors were treated by i.p injection of saline control; 60 or 180 mg/kg PDX on days 1, 4 and 7; 60 or 180 mg/kg PDX on days 1, 4 and 7 followed by 50 mg/kg leucovorin 24, 32 and 48 h after each PDX administration; 50 mg/kg leucovorin. Tumor volume (a) and body weight (b) were measured
Mentions: The effect of LV treatment on PDX efficacy and toxicity was examined using H2052 xenografts in nude mice (Fig. 3). Using 60 mg/kg as the equivalent clinical dose, tumor regression was seen both with and without LV treatment in this cohort. Efficacy was nearly identical, but mice that were treated with LV had less toxicity and bodyweight remained close to control animals.Fig. 3

Bottom Line: 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.High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, USA.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus