A novel taxane active against an orthotopically growing human glioma xenograft.
BACKGROUND
The development of effective chemotherapy for central nervous system tumors is hampered by the blood-brain barrier and by limited drug diffusion in the brain tissue. BAY 59-8862 is a new taxane analog that was selected and developed for its activity against tumors with a P-glycoprotein-mediated, multidrug-resistant phenotype. Because P-glycoprotein is implicated in limiting the access of drugs to central nervous system tumor targets, the objective of this study was to evaluate the ability of intravenously administered BAY 59-8862 to affect the growth of central nervous system tumors.


METHODS
The U-87 MG human glioma cell line was xenografted orthotopically (intracranially) in nude mice. Paclitaxel or BAY 59-8862 was delivered intravenously four times every fourth day, and antitumor efficacy was assessed by examining the effects on mouse survival time and by histologic examination of mouse brain. Drug levels in plasma and brain were determined according to a high-performance liquid chromatography method.


RESULTS
The analog was as potent as paclitaxel in inhibiting the proliferation of three human glioma cell lines (U-87 MG, SW1783, and GBM) and was as effective as paclitaxel in inhibiting the heterotopic (subcutaneous) tumor growth in nude mice of U-87 MG cells (tumor weight inhibition, approximately 60%). In contrast, BAY 59-8862 was more active than paclitaxel (P < 0.05 in two of three experiments) in increasing the survival time of mice that were injected orthotopically with U-87 MG cells. The results were supported by the pharmacokinetic data, which indicated a much higher (about 15-fold) brain:plasma level ratio in BAY 59-8862-treated animals compared with paclitaxel-treated animals.


CONCLUSIONS
The study provides evidence of an additional pharmacologic advantage of BAY 59-8862, i.e., the ability to affect the growth of intracranial tumors, probably due to the lack of recognition by the P-glycoprotein-mediated transport systems. The favorable behavior of BAY 59-8862 supports the potential interest in the analog for clinical studies in patients with brain tumors or metastases.
Laccabue
D
D
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Tortoreto
M
M
Veneroni
S
S
Perego
P
P
Scanziani
E
E
Zucchetti
M
M
Zaffaroni
M
M
D'Incalci
M
M
Bombardelli
E
E
Zunino
F
F
Pratesi
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000493:pharmacokinetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles; D007262:Infusions, Intravenous; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D043823:Taxoids; D014183:Transplantation, Heterologous
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D007211:Indoles; D043823:Taxoids; C055192:Bay 02752; C404743:IDN 5109; D017239:Paclitaxel