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Comparative Study
. 2009 Oct;64(5):993-9.
doi: 10.1007/s00280-009-0954-4. Epub 2009 Feb 17.

Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers

E Izbicka  1 , A Diaz, R Streeper, M Wick, D Campos, R Steffen, M Saunders
Affiliations
Comparative Study

Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers

E Izbicka et al. Cancer Chemother Pharmacol. 2009 Oct.

Abstract

Purpose: This study evaluated mechanistic differences of pralatrexate, methotrexate, and pemetrexed.

Methods: Inhibition of dihydrofolate reductase (DHFR) was quantified using recombinant human DHFR. Cellular uptake and folylpolyglutamate synthetase (FPGS) activity were determined using radiolabeled pralatrexate, methotrexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) was assessed using MV522 and NCI-H460 human NSCLC xenografts.

Results: Apparent K ( i ) values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. In vivo, pralatrexate showed superior anti-tumor activity in both NSCLC models, with more effective dose-dependent TGI in the more rapidly growing NCI-H460 xenografts.

Conclusions: Pralatrexate demonstrated a distinct mechanistic and anti-tumor activity profile relative to methotrexate and pemetrexed. Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models.

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Figures

Fig. 1
Fig. 1
Pralatrexate and methotrexate structures
Fig. 2
Fig. 2
Inhibition of DHFR activity by pralatrexate in a cell-free system. a Concentration dependence of DHFR activity. b–d Estimation of Ki app for DHFR inhibition by pralatrexate, methotrexate, and pemetrexed, respectively
Fig. 3
Fig. 3
A short-term uptake of radiolabeled antifolates in NCI-H460 cells Drugs were dosed for 15 or 60 min. White bars cells incubated with radiolabeled drug only, black bars cells incubated with radiolabeled drug plus excess unlabeled drug
Fig. 4
Fig. 4
Differential activity of the antifolates on tumor volume and body weight in NCI-H460 and MV522 human tumor xenografts. a Percent change in tumor volume. b Percent change in total body weight. PDX pralatrexate, MTX methotrexate, Alimta pemetrexed
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