In vitro anthracycline cross-resistance pattern in childhood acute lymphoblastic leukaemia.

E Klumper,Ah Loonen,Dr Huismans,R Pieters,Ml Den Boer,Ajp Veerman

doi:10.1038/bjc.1995.231

Abstract

Daunorubicin (DNR) is a major front-line drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Previously, we showed that in vitro resistance to DNR at diagnosis is related to a poor long-term clinical outcome in childhood ALL and that relapsed ALL samples are more resistant to DNR than untreated ALL samples. In cell line studies, idarubicin (IDR), aclarubicin (ACR) and mitoxantrone (MIT) showed a (partial) lack of cross-resistance to the conventional anthracyclines DNR and doxorubicin (DOX), but clinical studies in childhood ALL have been inconclusive about the suggested lack of cross-resistance. In the present study we determined the in vitro cross-resistance pattern between DNR, DOX, IDR, ACR and MIT in 48 untreated and 39 relapsed samples from children with ALL using the MTT assay. The relapsed ALL group was about twice as resistant to DNR, DOX, IDR, ACR and MTT as the untreated ALL group. Thus, resistance developed to all five drugs. We found a significant cross-resistance between DNR, DOX, IDR, ACR and MIT, although in some individual cases in vitro anthracycline cross-resistance was less pronounced. We conclude that IDR, ACR and MIT cannot circumvent in vitro resistance to DNR in childhood ALL. Clinical studies may still prove whether IDR, ACR or MIT has a more favourable toxicity profile than DNR.

Highlights

All drugs were further diluted with RPMI-1640
Microculture plates were prepared with serial 4-fold drug dilutions derived from these stock solutions, and the plates were stored at -20°C to facilitate large-scale testing
All children from the relapsed acute lymphoblastic leukaemia (ALL) group had previously been exposed to DNR and or DOX as part of multidrug front-line chemotherapy

Summary

Materials and methods

We tested the following drugs: DNR (Polyfarma, The Netherlands), DOX and IDR Received 5 October 1994: revised 1 Februars 1995; accepted 2 Februarv 1995 lands), MIT ACR was a generous gift from Lundbeck DNR, DOX and IDR were dissolved in distilled water. All drugs were further diluted with RPMI-1640 UK) and stored at - 20'C in stock solutions of 50gml-1' (MIT). L00 gml-' (DNR, IDR) and 400 g ml- l Microculture plates were prepared with serial 4-fold drug dilutions derived from these stock solutions, and the plates were stored at -20°C to facilitate large-scale testing. Without loss of in vitro anti-leukaemic efficacy of all drugs tested (data not shown) Anthracycines can be safely stored at - 20'C up to 9 months without decomposition (Scott et al.. 1986). and without loss of in vitro anti-leukaemic efficacy of all drugs tested (data not shown)

Leukaemic samples

LCwa activiti

In vitro chemosensitivitv

Results

Untreated Relapsed

DNR DOX