Retention of paclitaxel in cancer cells for 1 week in vivo and in vitro.
OBJECTIVE
Clinically, the administration of paclitaxel for ovarian cancer on a dose-dense weekly schedule, rather than the conventional every-3-week schedule, might demonstrate greater tumor-cell death. Here, we investigate the pharmacokinetics and the pharmacodynamics of weekly paclitaxel in cancer cells in vivo and in vitro.


METHODS
Paclitaxel concentrations were measured by HPLC, and apoptotic cells were detected by TUNEL assay in paclitaxel-pretreated cervical cancer cells treated with paclitaxel (10 ng/ml) and in the tissues of cervical cancer patients treated with weekly paclitaxel (60 mg/m2/week). Polymerized tubulin was detected with a tubulin polymerization assay, and the BrdU cell proliferation assay was used to assess the effect of paclitaxel.


RESULTS
Paclitaxel remained in the cancer tissues of six patients for 6 days after the last medication. In vitro, paclitaxel was retained in all cell lines for 24 h after its removal from the medium, and paclitaxel was still detectable in CaSki cells on day 7. Simultaneous treatment with depolymerizing drugs inhibited the retention of paclitaxel in cells and paclitaxel-induced polymerization of tubulin. After paclitaxel treatment, apoptotic cells were detected in cancer tissues and CaSki cells for 1 week. Under high magnification, apoptotic cells on day 7 after paclitaxel treatment showed multinucleation.


CONCLUSIONS
Paclitaxel is unusual in that it accumulates especially in cancer cells and induces apoptosis for 1 week in vivo and in vitro. On the other hand, paclitaxel could not be detected in cancer tissues after 2 weeks. The administration of paclitaxel on a weekly schedule, rather than the standard every-3-week schedule, might produce greater tumor-cell death.
Mori
Taisuke
T
Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-Ku, 602-8566, Kyoto, Japan.
Kinoshita
Yoshiyuki
Y
Watanabe
Ai
A
Yamaguchi
Takeshi
T
Hosokawa
Kenichi
K
Honjo
Hideo
H
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007044:Hysterectomy; D020287:In Situ Nick-End Labeling; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D050257:Tubulin Modulators / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D050257:Tubulin Modulators; D016190:Carboplatin; D017239:Paclitaxel