Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

YanPing Hu, Awtar Krishan, WeiJia Nie, Kasi S. Sridhar, Lawrence D. Mayer, Marcel Bally

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Pyrazoloacridine (NSC 366140, PD115934, PZA) is a new class of acridine anticancer agents under investigation in Phase II clinical trials in patients with advanced cancers. Although poor responses in patients to the treatment with PZA alone have been observed, this class of agents remains of interest because of its distinct mechanism of action from other topoisomerase poisons. Therefore, the combination of PZA with conventional anticancer agents presents an attractive approach to treat drug-resistant human tumors. In the present study, the cytotoxic effects of PZA combined with doxorubicin, topotecan, and etoposide were determined using paired parental and doxorubicin-resistant human colon carcinoma (SW-620 and SW620/AD-300) and breast cancer cell lines (MCF-7 and MCF-7/TH). Cytotoxicity was measured by soft agar clonogenic assays. Dose effect and combination effects were analyzed by the method of Chou and Talalay. The combination of PZA with doxorubicin, topotecan, and etoposide in fixed ratios demonstrated synergistic cytotoxicity on both SW-620 and SW620/AD-300 cell lines. The combination of PZA with doxorubicin also exhibited synergistic cytotoxicity against both MCF-7 and MCF-7/TH cell lines. The mechanism of synergism appeared independent of topoisomerase I and II inhibition, and interference with protein-DNA complexes. Strategies to define optimal drug combinations are proving to be of significant value when considering potential clinical applications of new and established agents.

Original languageEnglish
Pages (from-to)1160-1169
Number of pages10
JournalClinical Cancer Research
Volume10
Issue number3
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

Fingerprint

NSC 366140
Topotecan
Etoposide
Doxorubicin
Cell Line
Pharmaceutical Preparations
Antineoplastic Agents
Neoplasms
Acridines
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Phase II Clinical Trials
Poisons
MCF-7 Cells
Drug Combinations
Agar
Colon
Breast Neoplasms
Carcinoma
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells. / Hu, YanPing; Krishan, Awtar; Nie, WeiJia; Sridhar, Kasi S.; Mayer, Lawrence D.; Bally, Marcel.

In: Clinical Cancer Research, Vol. 10, No. 3, 01.02.2004, p. 1160-1169.

Research output: Contribution to journalArticle

Hu, YanPing ; Krishan, Awtar ; Nie, WeiJia ; Sridhar, Kasi S. ; Mayer, Lawrence D. ; Bally, Marcel. / Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 3. pp. 1160-1169.
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