Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers.
Cancer chemotherapy is believed to be impeded by multidrug resistance (MDR). Pluronic (triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), PEO-b-PPO-b-PEO) were previously shown to sensitize MDR tumors to antineoplastic agents. This study uses animal models of Lewis lung carcinoma (3LL-M27) and T-lymphocytic leukemia (P388/ADR and P388) derived solid tumors to delineate mechanisms of sensitization of MDR tumors by Pluronic P85 (P85) in vivo. First, non-invasive single photon emission computed tomography (SPECT) and tumor tissue radioactivity sampling demonstrate that intravenous co-administration of P85 with a Pgp substrate, 99Tc-sestamibi, greatly increases the tumor uptake of this substrate in the MDR tumors. Second, 31P magnetic resonance spectroscopy (31P-MRS) in live animals and tumor tissue sampling for ATP suggest that P85 and doxorubicin (Dox) formulations induce pronounced ATP depletion in MDR tumors. Third, these formulations are shown to increase tumor apoptosis in vivo by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and reverse transcription polymerase chain reaction (RT-PCR) for caspases 8 and 9. Altogether, formulation of Dox with P85 results in increased inhibition of the growth solid tumors in mice and represents novel and promising strategy for therapy of drug resistant cancers.
Batrakova
Elena V
EV
College of Pharmacy, Department of Pharmaceutical Sciences, 985830 Nebraska Medical Center, Omaha, NE 68198-5830, USA.
Li
Shu
S
Brynskikh
Anna M
AM
Sharma
Amit K
AK
Li
Yili
Y
Boska
Michael
M
Gong
Nan
N
Mosley
R Lee
RL
Alakhov
Valery Yu
VY
Gendelman
Howard E
HE
Kabanov
Alexander V
AV
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020442:Poloxamer / Q000494:pharmacology*; D015899:Tomography, Emission-Computed, Single-Photon
D020442:Poloxamer; D004317:Doxorubicin; D000255:Adenosine Triphosphate