Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukaemia line, K562.
Dexrazoxane combined with doxorubicin (+ 5-fluorouracil + cyclophosphamide - the FAC regime) leads to a significant decrease in doxorubicin cardiotoxicity and a significant increase in median survival time for patients with advanced breast cancer responsive to FAC. The reason for this increase in survival may be due to interference with the mechanism involved in the emergence of multidrug resistance (MDR). In order to test this hypothesis, we induced resistance to doxorubicin in the K562 cell line by growing cells in increasing concentrations of doxorubicin (10-30 nM) in the presence and absence of dexrazoxane (20 nM). The doxorubicin sensitivity of all resultant sublines was measured using the MTT assay. Flow cytometry was used to assess the MDR1 phenotype, measuring P-glycoprotein expression with MRK 16 antibody and drug accumulation in the presence and absence of PSC 833 for functional P-glycoprotein. Long-term growth in doxorubicin increased the cellular resistance (IC(50)) of K562 cells in a concentration-dependent manner (r(2 )= 0.908). Doxorubicin resistance was not induced in the presence of dexrazoxane (P< 0.0001) for several months. In parallel, the expression of functional P-glycoprotein was delayed after concomitant addition of dexrazoxane to the selecting medium (P< 0.001). Dexrazoxane did not act as a conventional modulator of P-glycoprotein. These results suggest that dexrazoxane may delay the development of MDR1, thus allowing responders to the FAC regime to continue to respond.
Sargent
J M
JM
Haematology Research, Pembury Hospital, Pembury, Kent TN2 4QJ, UK.
Williamson
C J
CJ
Yardley
C
C
Taylor
C G
CG
Hellmann
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells / Q000187:drug effects*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011929:Razoxane / Q000008:administration & dosage / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D003524:Cyclosporins; D012333:RNA, Messenger; D011929:Razoxane; D004317:Doxorubicin; C070272:valspodar; D003630:Daunorubicin