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Prednisolone Resistance in Childhood Acute Lymphoblastic
Leukemia: Vitro-Vivo Correlations and Cross-Resistance to Other
Drugs
G.J.L. Kaspers,
R. Pieters,
C.H. Van Zantwijk,
E.R. VanWering,
A. Van Der Does-Van Den Berg, and
A.J.P. Veerman
From the Department of Pediatric Hematology/Oncology, University
Hospital Vrije Universiteit, Amsterdam; and Dutch Childhood Leukemia
Study Group, The Hague, The Netherlands.
As an important determinant of response to
chemotherapy, accurate measurement of cellular drug resistance may
provide clinically relevant information. Our objectives in this study
were to determine the relationship between in vitro resistance to
prednisolone (PRD) measured with the colorimetric
methyl-thiazol-tetrazolium (MTT) assay, and (1) short-term clinical
response to systemic PRD monotherapy, (2) long-term clinical outcome
after combination chemotherapy within all patients and within the
subgroups of clinical good and poor responders to PRD, and (3) in vitro
resistance to 12 other drugs in 166 children with newly diagnosed acute
lymphoblastic leukemia (ALL). The 12 clinical poor PRD responders had
ALL cells that were median 88-fold more in vitro resistant to PRD than
131 good responders (P = .013). Within all patients,
increased in vitro resistance to PRD predicted a significantly worse
long-term clinical outcome, at analyses with and without stratification for clinical PRD response, and at multivariate analysis (P  .001). Within both the clinical good and poor responder subgroups,
increased in vitro resistance to PRD was associated with a worse
outcome, which was significant within the group of clinical good
responders (P < .001). LC50 values, ie, lethal
concentrations to 50% of ALL cells, for PRD and each other drug
correlated significantly with those of all other 12 drugs, with an
average correlation coefficient of 0.44 (standard deviation 0.05). The
highest correlations were found between structurally related drugs. In
conclusion, in vitro resistance to PRD was significantly related to the
short-term and long-term clinical response to chemotherapy, the latter
also within the subgroup of clinical good responders to PRD. There was
a more general in vitro cross-resistance between anticancer drugs in
childhood ALL, although drug-specific activities were recognized.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 259-266
© 1998 by The American Society of Hematology.
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