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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

Leucovorin (LV) may abrogate pralatrexate (PDX) activity through three mechanisms. i Competition for reduced folate carrier type 1 (RFC) transport into cell. ii Competition for polyglutamylation, a retention and activity marker, by folylpolyglutamate synthase (FPGS). iii Provides an alternate source of tetrahydrofolate, working around PDX inhibition of dihydrofolate reductase (DHFR)
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Fig1: Leucovorin (LV) may abrogate pralatrexate (PDX) activity through three mechanisms. i Competition for reduced folate carrier type 1 (RFC) transport into cell. ii Competition for polyglutamylation, a retention and activity marker, by folylpolyglutamate synthase (FPGS). iii Provides an alternate source of tetrahydrofolate, working around PDX inhibition of dihydrofolate reductase (DHFR)

Mentions: Adverse events associated with antifolates can be severe, commonly mucositis and leukopenia. A strategy to avoid toxicity and still provide clinical benefit is the inclusion of leucovorin (LV) in high-dose MTX regimens [7]. LV is a stable, reduced form of folate that is converted to tetrahydrofolate without requiring DHFR, thus bypassing the inhibition of tetrahydrofolate synthesis by MTX and PDX. LV also competes for binding with antifolates at the reduced folate carrier, and when converted to tetrahydrofolate, competes with antifolates for polyglutamylation (Fig. 1).Fig. 1


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)

Leucovorin (LV) may abrogate pralatrexate (PDX) activity through three mechanisms. i Competition for reduced folate carrier type 1 (RFC) transport into cell. ii Competition for polyglutamylation, a retention and activity marker, by folylpolyglutamate synthase (FPGS). iii Provides an alternate source of tetrahydrofolate, working around PDX inhibition of dihydrofolate reductase (DHFR)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Leucovorin (LV) may abrogate pralatrexate (PDX) activity through three mechanisms. i Competition for reduced folate carrier type 1 (RFC) transport into cell. ii Competition for polyglutamylation, a retention and activity marker, by folylpolyglutamate synthase (FPGS). iii Provides an alternate source of tetrahydrofolate, working around PDX inhibition of dihydrofolate reductase (DHFR)
Mentions: Adverse events associated with antifolates can be severe, commonly mucositis and leukopenia. A strategy to avoid toxicity and still provide clinical benefit is the inclusion of leucovorin (LV) in high-dose MTX regimens [7]. LV is a stable, reduced form of folate that is converted to tetrahydrofolate without requiring DHFR, thus bypassing the inhibition of tetrahydrofolate synthesis by MTX and PDX. LV also competes for binding with antifolates at the reduced folate carrier, and when converted to tetrahydrofolate, competes with antifolates for polyglutamylation (Fig. 1).Fig. 1

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