In vivo antitumor activity of S16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts.
New active drugs are needed for the treatment of primary brain tumors in both children and adults. S16020 is a cytotoxic olivacine derivative that inhibits topoisomerase II. The aim of the study was to determine its antitumor activity in athymic mice bearing subcutaneous medulloblastoma (IGRM33, 34, 57) and glioblastoma (IGRG88, 93, 121) xenografts treated at an advanced stage of tumor growth in comparison with that of doxorubicin. Animals were randomly assigned to receive i.v. S16020 or doxorubicin weekly for three consecutive weeks. The optimal dose was 80 mg/kg per week. S16020 demonstrated a significant antitumor activity in two out of three medulloblastoma xenografts. IGRM57 xenografts were highly sensitive with 100% tumor regressions and a tumor growth delay (TGD) of 102 days, while one of eight IGRM34 xenografts showed a partial regression with a TGD of 16 days. Doxorubicin was significantly more active than S16020 in these two models. IGRM33, a model established from a tumor in relapse after chemotherapy and radiotherapy, was refractory to both drugs. S16020 demonstrated a significant antitumor activity in the three glioblastoma xenografts evaluated. The wild-type p53 IGRG93 xenograft was highly sensitive with 100% tumor regressions and a TGD of 54 days. IGRG121 (wt p53) and IGRG88 (mutant p53) were moderately sensitive with TGDs of 33 and 23 days, respectively. Doxorubicin showed greater activity in two of these models. All six xenografts exhibited low expression of mdr1 as quantitated by RT-PCR, and no correlation was found with the activity of either drug. Conversely, a low activity of the two drugs was significantly associated with a high expression of MRP1 in medulloblastomas. Finally, no relationship was observed between drug sensitivity to either drug and expression of their target, topoisomerase IIalpha. In conclusion, S16020 and doxorubicin showed significant antitumor activity in brain tumor xenografts treated at an advanced stage of tumor growth. Their activity was related to MRP1 expression in medulloblastomas.
Vassal
Gilles
G
UPRES EA 3535 Pharmacology and New Treatments of Cancers, Institut Gustave-Roussy, Villejuif, France. gvassal@igr.fr
Merlin
Jean-Louis
JL
Terrier-Lacombe
Marie-José
MJ
Grill
Jacques
J
Parker
Fabrice
F
Sainte-Rose
Christian
C
Aubert
Geneviève
G
Morizet
Jackie
J
Sévenet
Nicolas
N
Poullain
Marie-Gwenaëlle
MG
Lucas
Catherine
C
Kalifa
Chantal
C
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D004317:Doxorubicin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
D002227:Carbazoles; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; C117470:NSC 659687; C421109:multidrug resistance-associated protein 1