Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice

Hideto To, Mikiko Shin, Mayumi Tabuchi, Hiromi Sakaguchi, Ayako Takeuchi, Naoya Matsunaga, Shun Higuchi, Shigehiro Ohdo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: Although the combination of Adriamycin (ADR) and docetaxel (DOC) showed a better cure rate against metastatic breast cancer in a clinical study, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve the antitumor effects. Experimental Design: Both ADR and DOC were administered simultaneously in the simultaneous-dosing group (ADR/DOC), whereas in the intermittent-dosing groups (ADR-DOC and DOC-ADR), the second drug was administered 12 h after the first drug. Leukocyte counts and survival were measured to estimate adverse effects. After administration, ADR and DOC concentrations in blood, myelocyte cells, and heart were determined. To clarify the antitumor effect, tumor growth was measured in Ehrlich-cell-bearing mice after the initiation of drug injections. Results: The simultaneous-dosing group showed severe leukopenia compared with the saline-treated group. However, the toxicity was reduced in the intermittent-dosing groups. The DOC-ADR group showed the best survival rate in the dosing groups. In the pharmacokinetic study, ADR and DOC concentrations in plasma, myelocyte cells, and the heart were markedly higher in the simultaneous-dosing group than the intermittent-dosing groups. These results indicate that pharmacokinetic interactions may contribute to the change in leukopenia induced by concurrent administration of ADR and DOC. The antitumor effect in the DOC-ADR group was the highest in the dosing groups. Conclusions: In the present study, the findings suggest that ADR administered 12 h after DOC injection (DOC-ADR group) not only inhibits tumor growth more strongly but also significantly reduces leukopenia compared with results for the simultaneous-dosing (ADR/DOC) group and significantly reduced the number of toxic deaths compared with the other groups.

Original languageEnglish
Pages (from-to)762-769
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number2
DOIs
Publication statusPublished - Jan 15 2004

Fingerprint

docetaxel
Doxorubicin
Appointments and Schedules
Leukopenia
Granulocyte Precursor Cells
Pharmacokinetics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice. / To, Hideto; Shin, Mikiko; Tabuchi, Mayumi; Sakaguchi, Hiromi; Takeuchi, Ayako; Matsunaga, Naoya; Higuchi, Shun; Ohdo, Shigehiro.

In: Clinical Cancer Research, Vol. 10, No. 2, 15.01.2004, p. 762-769.

Research output: Contribution to journalArticle

To, Hideto ; Shin, Mikiko ; Tabuchi, Mayumi ; Sakaguchi, Hiromi ; Takeuchi, Ayako ; Matsunaga, Naoya ; Higuchi, Shun ; Ohdo, Shigehiro. / Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 2. pp. 762-769.
@article{ac22681260b44a519d6c5944e553c15d,
title = "Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice",
abstract = "Purpose: Although the combination of Adriamycin (ADR) and docetaxel (DOC) showed a better cure rate against metastatic breast cancer in a clinical study, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve the antitumor effects. Experimental Design: Both ADR and DOC were administered simultaneously in the simultaneous-dosing group (ADR/DOC), whereas in the intermittent-dosing groups (ADR-DOC and DOC-ADR), the second drug was administered 12 h after the first drug. Leukocyte counts and survival were measured to estimate adverse effects. After administration, ADR and DOC concentrations in blood, myelocyte cells, and heart were determined. To clarify the antitumor effect, tumor growth was measured in Ehrlich-cell-bearing mice after the initiation of drug injections. Results: The simultaneous-dosing group showed severe leukopenia compared with the saline-treated group. However, the toxicity was reduced in the intermittent-dosing groups. The DOC-ADR group showed the best survival rate in the dosing groups. In the pharmacokinetic study, ADR and DOC concentrations in plasma, myelocyte cells, and the heart were markedly higher in the simultaneous-dosing group than the intermittent-dosing groups. These results indicate that pharmacokinetic interactions may contribute to the change in leukopenia induced by concurrent administration of ADR and DOC. The antitumor effect in the DOC-ADR group was the highest in the dosing groups. Conclusions: In the present study, the findings suggest that ADR administered 12 h after DOC injection (DOC-ADR group) not only inhibits tumor growth more strongly but also significantly reduces leukopenia compared with results for the simultaneous-dosing (ADR/DOC) group and significantly reduced the number of toxic deaths compared with the other groups.",
author = "Hideto To and Mikiko Shin and Mayumi Tabuchi and Hiromi Sakaguchi and Ayako Takeuchi and Naoya Matsunaga and Shun Higuchi and Shigehiro Ohdo",
year = "2004",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-1000-03",
language = "English",
volume = "10",
pages = "762--769",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice

AU - To, Hideto

AU - Shin, Mikiko

AU - Tabuchi, Mayumi

AU - Sakaguchi, Hiromi

AU - Takeuchi, Ayako

AU - Matsunaga, Naoya

AU - Higuchi, Shun

AU - Ohdo, Shigehiro

PY - 2004/1/15

Y1 - 2004/1/15

N2 - Purpose: Although the combination of Adriamycin (ADR) and docetaxel (DOC) showed a better cure rate against metastatic breast cancer in a clinical study, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve the antitumor effects. Experimental Design: Both ADR and DOC were administered simultaneously in the simultaneous-dosing group (ADR/DOC), whereas in the intermittent-dosing groups (ADR-DOC and DOC-ADR), the second drug was administered 12 h after the first drug. Leukocyte counts and survival were measured to estimate adverse effects. After administration, ADR and DOC concentrations in blood, myelocyte cells, and heart were determined. To clarify the antitumor effect, tumor growth was measured in Ehrlich-cell-bearing mice after the initiation of drug injections. Results: The simultaneous-dosing group showed severe leukopenia compared with the saline-treated group. However, the toxicity was reduced in the intermittent-dosing groups. The DOC-ADR group showed the best survival rate in the dosing groups. In the pharmacokinetic study, ADR and DOC concentrations in plasma, myelocyte cells, and the heart were markedly higher in the simultaneous-dosing group than the intermittent-dosing groups. These results indicate that pharmacokinetic interactions may contribute to the change in leukopenia induced by concurrent administration of ADR and DOC. The antitumor effect in the DOC-ADR group was the highest in the dosing groups. Conclusions: In the present study, the findings suggest that ADR administered 12 h after DOC injection (DOC-ADR group) not only inhibits tumor growth more strongly but also significantly reduces leukopenia compared with results for the simultaneous-dosing (ADR/DOC) group and significantly reduced the number of toxic deaths compared with the other groups.

AB - Purpose: Although the combination of Adriamycin (ADR) and docetaxel (DOC) showed a better cure rate against metastatic breast cancer in a clinical study, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve the antitumor effects. Experimental Design: Both ADR and DOC were administered simultaneously in the simultaneous-dosing group (ADR/DOC), whereas in the intermittent-dosing groups (ADR-DOC and DOC-ADR), the second drug was administered 12 h after the first drug. Leukocyte counts and survival were measured to estimate adverse effects. After administration, ADR and DOC concentrations in blood, myelocyte cells, and heart were determined. To clarify the antitumor effect, tumor growth was measured in Ehrlich-cell-bearing mice after the initiation of drug injections. Results: The simultaneous-dosing group showed severe leukopenia compared with the saline-treated group. However, the toxicity was reduced in the intermittent-dosing groups. The DOC-ADR group showed the best survival rate in the dosing groups. In the pharmacokinetic study, ADR and DOC concentrations in plasma, myelocyte cells, and the heart were markedly higher in the simultaneous-dosing group than the intermittent-dosing groups. These results indicate that pharmacokinetic interactions may contribute to the change in leukopenia induced by concurrent administration of ADR and DOC. The antitumor effect in the DOC-ADR group was the highest in the dosing groups. Conclusions: In the present study, the findings suggest that ADR administered 12 h after DOC injection (DOC-ADR group) not only inhibits tumor growth more strongly but also significantly reduces leukopenia compared with results for the simultaneous-dosing (ADR/DOC) group and significantly reduced the number of toxic deaths compared with the other groups.

UR - http://www.scopus.com/inward/record.url?scp=0842289261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0842289261&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-1000-03

DO - 10.1158/1078-0432.CCR-1000-03

M3 - Article

C2 - 14760099

AN - SCOPUS:0842289261

VL - 10

SP - 762

EP - 769

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -