Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer

Characterization and mechanism of resistance

Fumihiko Kanzawa, Yoshikazu Sugimoto, Koichi Minato, Kazuo Kasahara, Masami Bungo, Kazuhiko Nakagawa, Yasuhiro Fujiwara, Leroy F. Liu, Nagahiro Saijo

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent, and a good candidate for clinical trials because of higher antitumor activity, less toxicity, and high aqueous solubility. CPT-11 is known to be altered into an active form, SN-38, by esterase in in vivo. CPT-11-resistant cells (PC-7/CPT) established from a human non-small cell lung cancer cell (PC-7) by stepwise, continuous treatment with CPT-11 exhibit about a 10-fold increase in resistance to the drug. CPT-11-resistant cells show a moderate cross-resistance to camptothecin (x8.6) and SN-38 (x8.6), and weak cross-resistance to Adriamycin (x2.2) and 5-fluorouracil (x2.4). The comparative studies between the parent (PC-7) and resistant (PC-7/CPT) cell lines with respect to their growth characterization shows a longer cell doubling time (45.8 versus 35.5 h), a lower cloning efficiency (3.2 versus 7.1%), and a lower population of S-phase cells (26.4 versus 36.0%) in the CPT-11-resistant cells. This observation may partly explain the resistance to CPT-11, a drug whose activity is cell cycle specific. Accumulation of CPT-11 is nearly the same in both cell lines. However, the intracellular concentration of SN-38 formed in the parent cells was 2-fold greater than in the CPT-11-resistant cells. This alteration may affect to some extent to the resistance. As assayed by relaxation of supercoiled plasmid DNA, the total activity of DNA topoisomerase I from the CPT-11-resistant cells was shown to be reduced to one-fourth its level in sensitive cells. The reduced activity was caused by a reduction of amount of DNA topoisomerase I. Furthermore, the enzyme from the resistant cells was shown to be 5-fold more resistant to CPT-11 than the enzyme from the parent cells. Thus, decreased total activity of topoisomerase I may play an important role in cellular resistance to CPT-11, and it appears that this decreased activity is due to a resistant form of topoisomerase I in CPT-11 resistant cells.

Original languageEnglish
Pages (from-to)5919-5924
Number of pages6
JournalCancer Research
Volume50
Issue number18
Publication statusPublished - 1990 Sep 15
Externally publishedYes

Fingerprint

irinotecan
Camptothecin
Non-Small Cell Lung Carcinoma
Cell Line
Type I DNA Topoisomerase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer : Characterization and mechanism of resistance. / Kanzawa, Fumihiko; Sugimoto, Yoshikazu; Minato, Koichi; Kasahara, Kazuo; Bungo, Masami; Nakagawa, Kazuhiko; Fujiwara, Yasuhiro; Liu, Leroy F.; Saijo, Nagahiro.

In: Cancer Research, Vol. 50, No. 18, 15.09.1990, p. 5919-5924.

Research output: Contribution to journalArticle

Kanzawa, F, Sugimoto, Y, Minato, K, Kasahara, K, Bungo, M, Nakagawa, K, Fujiwara, Y, Liu, LF & Saijo, N 1990, 'Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer: Characterization and mechanism of resistance', Cancer Research, vol. 50, no. 18, pp. 5919-5924.
Kanzawa, Fumihiko ; Sugimoto, Yoshikazu ; Minato, Koichi ; Kasahara, Kazuo ; Bungo, Masami ; Nakagawa, Kazuhiko ; Fujiwara, Yasuhiro ; Liu, Leroy F. ; Saijo, Nagahiro. / Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer : Characterization and mechanism of resistance. In: Cancer Research. 1990 ; Vol. 50, No. 18. pp. 5919-5924.
@article{d8201a8057bb460c981f39920bfc9d65,
title = "Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer: Characterization and mechanism of resistance",
abstract = "Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent, and a good candidate for clinical trials because of higher antitumor activity, less toxicity, and high aqueous solubility. CPT-11 is known to be altered into an active form, SN-38, by esterase in in vivo. CPT-11-resistant cells (PC-7/CPT) established from a human non-small cell lung cancer cell (PC-7) by stepwise, continuous treatment with CPT-11 exhibit about a 10-fold increase in resistance to the drug. CPT-11-resistant cells show a moderate cross-resistance to camptothecin (x8.6) and SN-38 (x8.6), and weak cross-resistance to Adriamycin (x2.2) and 5-fluorouracil (x2.4). The comparative studies between the parent (PC-7) and resistant (PC-7/CPT) cell lines with respect to their growth characterization shows a longer cell doubling time (45.8 versus 35.5 h), a lower cloning efficiency (3.2 versus 7.1{\%}), and a lower population of S-phase cells (26.4 versus 36.0{\%}) in the CPT-11-resistant cells. This observation may partly explain the resistance to CPT-11, a drug whose activity is cell cycle specific. Accumulation of CPT-11 is nearly the same in both cell lines. However, the intracellular concentration of SN-38 formed in the parent cells was 2-fold greater than in the CPT-11-resistant cells. This alteration may affect to some extent to the resistance. As assayed by relaxation of supercoiled plasmid DNA, the total activity of DNA topoisomerase I from the CPT-11-resistant cells was shown to be reduced to one-fourth its level in sensitive cells. The reduced activity was caused by a reduction of amount of DNA topoisomerase I. Furthermore, the enzyme from the resistant cells was shown to be 5-fold more resistant to CPT-11 than the enzyme from the parent cells. Thus, decreased total activity of topoisomerase I may play an important role in cellular resistance to CPT-11, and it appears that this decreased activity is due to a resistant form of topoisomerase I in CPT-11 resistant cells.",
author = "Fumihiko Kanzawa and Yoshikazu Sugimoto and Koichi Minato and Kazuo Kasahara and Masami Bungo and Kazuhiko Nakagawa and Yasuhiro Fujiwara and Liu, {Leroy F.} and Nagahiro Saijo",
year = "1990",
month = "9",
day = "15",
language = "English",
volume = "50",
pages = "5919--5924",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer

T2 - Characterization and mechanism of resistance

AU - Kanzawa, Fumihiko

AU - Sugimoto, Yoshikazu

AU - Minato, Koichi

AU - Kasahara, Kazuo

AU - Bungo, Masami

AU - Nakagawa, Kazuhiko

AU - Fujiwara, Yasuhiro

AU - Liu, Leroy F.

AU - Saijo, Nagahiro

PY - 1990/9/15

Y1 - 1990/9/15

N2 - Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent, and a good candidate for clinical trials because of higher antitumor activity, less toxicity, and high aqueous solubility. CPT-11 is known to be altered into an active form, SN-38, by esterase in in vivo. CPT-11-resistant cells (PC-7/CPT) established from a human non-small cell lung cancer cell (PC-7) by stepwise, continuous treatment with CPT-11 exhibit about a 10-fold increase in resistance to the drug. CPT-11-resistant cells show a moderate cross-resistance to camptothecin (x8.6) and SN-38 (x8.6), and weak cross-resistance to Adriamycin (x2.2) and 5-fluorouracil (x2.4). The comparative studies between the parent (PC-7) and resistant (PC-7/CPT) cell lines with respect to their growth characterization shows a longer cell doubling time (45.8 versus 35.5 h), a lower cloning efficiency (3.2 versus 7.1%), and a lower population of S-phase cells (26.4 versus 36.0%) in the CPT-11-resistant cells. This observation may partly explain the resistance to CPT-11, a drug whose activity is cell cycle specific. Accumulation of CPT-11 is nearly the same in both cell lines. However, the intracellular concentration of SN-38 formed in the parent cells was 2-fold greater than in the CPT-11-resistant cells. This alteration may affect to some extent to the resistance. As assayed by relaxation of supercoiled plasmid DNA, the total activity of DNA topoisomerase I from the CPT-11-resistant cells was shown to be reduced to one-fourth its level in sensitive cells. The reduced activity was caused by a reduction of amount of DNA topoisomerase I. Furthermore, the enzyme from the resistant cells was shown to be 5-fold more resistant to CPT-11 than the enzyme from the parent cells. Thus, decreased total activity of topoisomerase I may play an important role in cellular resistance to CPT-11, and it appears that this decreased activity is due to a resistant form of topoisomerase I in CPT-11 resistant cells.

AB - Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent, and a good candidate for clinical trials because of higher antitumor activity, less toxicity, and high aqueous solubility. CPT-11 is known to be altered into an active form, SN-38, by esterase in in vivo. CPT-11-resistant cells (PC-7/CPT) established from a human non-small cell lung cancer cell (PC-7) by stepwise, continuous treatment with CPT-11 exhibit about a 10-fold increase in resistance to the drug. CPT-11-resistant cells show a moderate cross-resistance to camptothecin (x8.6) and SN-38 (x8.6), and weak cross-resistance to Adriamycin (x2.2) and 5-fluorouracil (x2.4). The comparative studies between the parent (PC-7) and resistant (PC-7/CPT) cell lines with respect to their growth characterization shows a longer cell doubling time (45.8 versus 35.5 h), a lower cloning efficiency (3.2 versus 7.1%), and a lower population of S-phase cells (26.4 versus 36.0%) in the CPT-11-resistant cells. This observation may partly explain the resistance to CPT-11, a drug whose activity is cell cycle specific. Accumulation of CPT-11 is nearly the same in both cell lines. However, the intracellular concentration of SN-38 formed in the parent cells was 2-fold greater than in the CPT-11-resistant cells. This alteration may affect to some extent to the resistance. As assayed by relaxation of supercoiled plasmid DNA, the total activity of DNA topoisomerase I from the CPT-11-resistant cells was shown to be reduced to one-fourth its level in sensitive cells. The reduced activity was caused by a reduction of amount of DNA topoisomerase I. Furthermore, the enzyme from the resistant cells was shown to be 5-fold more resistant to CPT-11 than the enzyme from the parent cells. Thus, decreased total activity of topoisomerase I may play an important role in cellular resistance to CPT-11, and it appears that this decreased activity is due to a resistant form of topoisomerase I in CPT-11 resistant cells.

UR - http://www.scopus.com/inward/record.url?scp=0025084410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025084410&partnerID=8YFLogxK

M3 - Article

VL - 50

SP - 5919

EP - 5924

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -