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Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo.

AbstractINTRODUCTION:
Patupilone is a microtubule stabilizer (MTS) currently in clinical development. Here, we evaluate the anti-cancer activity in vitro and in vivo in comparison to paclitaxel and describe the pharmacokinetics (PK) of patupilone in tumor-bearing nude mice and rats.
METHODS:
The potency in vitro of patupilone and two other MTS, paclitaxel and ixabepilone, was determined using human colon carcinoma cell lines with low (HCT-116, HT-29, RKO) and high (HCT-15) P-glycoprotein expression (P-gp), as well as two multi-drug resistance (MDR) model cell pairs, MCF7/ADR and KB-8511 cells and their respective drug-sensitive parental counterparts. The PK of patupilone was investigated in nude mice bearing HCT-15 or HT-29 xenografts and in rats bearing s.c. pancreatic CA20498 tumors or A15 glioma tumors. Anti-cancer activity in vivo was compared to that of paclitaxel using three different human tumor colon models. The retention and efficacy of patupilone was compared in small and large HT-29 xenografts whose vascularity was determined by non-invasive magnetic resonance imaging.
RESULTS:
Patupilone was highly potent in vitro against four different colon carcinoma cell lines including those showing multi-drug-resistance. In contrast, paclitaxel and ixabepilone displayed significantly reduced activity with markedly increased resistance factors. In both rats and mice, a single i.v. bolus injection of patupilone (1.5-4 mg/kg) rapidly distributed from plasma to all tissues and was slowly eliminated from muscle, liver and small intestine, but showed longer retention in tumor and brain with no apparent elimination over 24 h. Patupilone showed significant activity against three human colon tumor models in vivo, unlike paclitaxel, which only had activity against low P-gp expressing tumors. In HT-29 tumors, patupilone activity and retention were independent of tumor size, blood volume and flow.
CONCLUSIONS:
The high potency of patupilone, which is not affected by P-gp expression either in vitro or in vivo, and favorable PK, independent of tumor vascularity, suggest that it should show significant activity in colorectal cancer and in other indications where high P-gp expression may compromise taxane activity.
AuthorsTerence O'Reilly, Markus Wartmann, Joseph Brueggen, Peter R Allegrini, Andreas Floersheimer, Michel Maira, Paul M J McSheehy
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 6 Pg. 1045-54 (Nov 2008) ISSN: 1432-0843 [Electronic] Germany
PMID18301895 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Epothilones
  • Neoplasm Proteins
  • ixabepilone
  • Paclitaxel
  • epothilone B
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
  • Animals
  • Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Carcinoma (blood supply, drug therapy, metabolism, pathology)
  • Cell Line, Tumor (drug effects, metabolism)
  • Colonic Neoplasms (blood supply, drug therapy, metabolism, pathology)
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Epothilones (pharmacokinetics, pharmacology, therapeutic use)
  • Female
  • Glioma (drug therapy, metabolism, pathology)
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Nude
  • Microtubules (drug effects)
  • Neoplasm Proteins (metabolism)
  • Paclitaxel (pharmacology, therapeutic use)
  • Pancreatic Neoplasms (drug therapy, metabolism, pathology)
  • Rats
  • Rats, Inbred Lew
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

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