Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates

M G Rots, R Pieters, G J Peters, C H van Zantwijk, R Mauritz, P Noordhuis, J C Willey, K Hählen, U Creutzig, G Janka-Schaub, G J Kaspers, A J Veerman, G Jansen

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Abstract

Cellular methotrexate (MTX) resistance may cause treatment failure in childhood common/preB-acute lymphoblastic leukemia (c/preB-ALL), T-lineage ALL (T-ALL), and acute myeloid leukemia (AML). The ex vivo potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89, multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied via in situ inhibition of thymidylate synthase (TS). After short-term exposure, relapsed c/preB-ALL (rALL, n = 21), T-ALL (n = 22), and AML (n = 22) were 3-fold, 10-fold, and 6-fold less sensitive to MTX (P </=.01) compared with initial c/preB-ALL (n = 43). This difference in resistance was not observed for TMQ. Also for GW1843U89 and MTA, no resistance was observed in rALL and AML compared with c/preB-ALL. T-ALL compared with c/preB-ALL tended to be less resistant to GW1843U89 (3-fold) and MTA (6-fold) than to MTX (10-fold) (P =.06). Raltitrexed was more active against c/preB-ALL compared with the other subtypes. After 21 hours continuous incubation, T-ALL and AML samples were equally sensitive as c/preB-ALL to MTX, but rALL was 3-fold resistant to MTX compared with initial c/preB-ALL (P =.003). The resistance of rALL was circumvented by TMQ (1-fold; P =.03) and GW1843U89 (1.4-fold; P =. 004). Novel antifolates, except MTA, displayed a more potent TS inhibition than MTX during continuous exposure. These results suggest that MTX resistance in AML and T-ALL can be circumvented by continuous exposure, and that novel antifolates should be explored further for MTX-resistant T-ALL, rALL, and AML cells.

Original languageEnglish
Pages (from-to)3121-8
Number of pages8
JournalBlood
Volume94
Issue number9
Publication statusPublished - 1 Nov 1999

Cite this

Rots, M. G., Pieters, R., Peters, G. J., van Zantwijk, C. H., Mauritz, R., Noordhuis, P., ... Jansen, G. (1999). Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. Blood, 94(9), 3121-8.