Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro

Carlo Aschele, Chiara Baldo, Alberto F. Sobrero, Domizia Debernardis, William G. Bornmann, Joseph R. Bertino

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The quinazoline folate analogue raltitrexed (ZD1694; Tomudex) and the camptothecin derivative irinotecan are two new agents showing clinical activity against colorectal cancer. To identify the optimal conditions to achieve synergistic cytotoxicity before the clinical development of their combination, we explored the interactions between ZD1694 and the active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38), in vitro. Cytotoxicity was evaluated with a clonogenic assay using the human colon cancer cell line HCT-8. Different schedules of administration and different dose ratios of the two agents were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median- effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). Sequential short-term (1 and 4-h) exposures to SN- 38 followed by ZD1694 resulted in synergistic cytotoxicity at broad dose- effect ranges. At a high level of cell kill, the synergism was greater when either equiactive doses of the two agents or higher relative doses of ZD1694 were used. A 24-h interval between exposure to SN-38 and ZD1694 significantly enhanced the magnitude of the synergy (P = 0.001). The opposite sequence or simultaneous exposures produced significantly less potentiation or nearly additive interactions (P = 0.0006 and P <0.0001). The synergism was completely lost under conditions of more prolonged drug exposure (24-h continuous exposure). In conclusion, in this in vitro model of human colon cancer, ZD1694 and SN-38 produced synergistic cytotoxicity. Our findings support the clinical use of this combination and provide a rationale for a clinical trial using sequential short-term exposures to equiactive doses of SN-38 and ZD1694 administered sequentially with a 24-h interval.

Original languageEnglish
Pages (from-to)1323-1330
Number of pages8
JournalClinical Cancer Research
Volume4
Issue number5
Publication statusPublished - May 1998

Fingerprint

irinotecan
Colonic Neoplasms
Appointments and Schedules
Camptothecin
Quinazolines
In Vitro Techniques
raltitrexed

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Aschele, C., Baldo, C., Sobrero, A. F., Debernardis, D., Bornmann, W. G., & Bertino, J. R. (1998). Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. Clinical Cancer Research, 4(5), 1323-1330.

Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. / Aschele, Carlo; Baldo, Chiara; Sobrero, Alberto F.; Debernardis, Domizia; Bornmann, William G.; Bertino, Joseph R.

In: Clinical Cancer Research, Vol. 4, No. 5, 05.1998, p. 1323-1330.

Research output: Contribution to journalArticle

Aschele, C, Baldo, C, Sobrero, AF, Debernardis, D, Bornmann, WG & Bertino, JR 1998, 'Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro', Clinical Cancer Research, vol. 4, no. 5, pp. 1323-1330.
Aschele, Carlo ; Baldo, Chiara ; Sobrero, Alberto F. ; Debernardis, Domizia ; Bornmann, William G. ; Bertino, Joseph R. / Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 5. pp. 1323-1330.
@article{d0ec142c041e4dcda87ea36beb467836,
title = "Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro",
abstract = "The quinazoline folate analogue raltitrexed (ZD1694; Tomudex) and the camptothecin derivative irinotecan are two new agents showing clinical activity against colorectal cancer. To identify the optimal conditions to achieve synergistic cytotoxicity before the clinical development of their combination, we explored the interactions between ZD1694 and the active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38), in vitro. Cytotoxicity was evaluated with a clonogenic assay using the human colon cancer cell line HCT-8. Different schedules of administration and different dose ratios of the two agents were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median- effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). Sequential short-term (1 and 4-h) exposures to SN- 38 followed by ZD1694 resulted in synergistic cytotoxicity at broad dose- effect ranges. At a high level of cell kill, the synergism was greater when either equiactive doses of the two agents or higher relative doses of ZD1694 were used. A 24-h interval between exposure to SN-38 and ZD1694 significantly enhanced the magnitude of the synergy (P = 0.001). The opposite sequence or simultaneous exposures produced significantly less potentiation or nearly additive interactions (P = 0.0006 and P <0.0001). The synergism was completely lost under conditions of more prolonged drug exposure (24-h continuous exposure). In conclusion, in this in vitro model of human colon cancer, ZD1694 and SN-38 produced synergistic cytotoxicity. Our findings support the clinical use of this combination and provide a rationale for a clinical trial using sequential short-term exposures to equiactive doses of SN-38 and ZD1694 administered sequentially with a 24-h interval.",
author = "Carlo Aschele and Chiara Baldo and Sobrero, {Alberto F.} and Domizia Debernardis and Bornmann, {William G.} and Bertino, {Joseph R.}",
year = "1998",
month = "5",
language = "English",
volume = "4",
pages = "1323--1330",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro

AU - Aschele, Carlo

AU - Baldo, Chiara

AU - Sobrero, Alberto F.

AU - Debernardis, Domizia

AU - Bornmann, William G.

AU - Bertino, Joseph R.

PY - 1998/5

Y1 - 1998/5

N2 - The quinazoline folate analogue raltitrexed (ZD1694; Tomudex) and the camptothecin derivative irinotecan are two new agents showing clinical activity against colorectal cancer. To identify the optimal conditions to achieve synergistic cytotoxicity before the clinical development of their combination, we explored the interactions between ZD1694 and the active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38), in vitro. Cytotoxicity was evaluated with a clonogenic assay using the human colon cancer cell line HCT-8. Different schedules of administration and different dose ratios of the two agents were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median- effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). Sequential short-term (1 and 4-h) exposures to SN- 38 followed by ZD1694 resulted in synergistic cytotoxicity at broad dose- effect ranges. At a high level of cell kill, the synergism was greater when either equiactive doses of the two agents or higher relative doses of ZD1694 were used. A 24-h interval between exposure to SN-38 and ZD1694 significantly enhanced the magnitude of the synergy (P = 0.001). The opposite sequence or simultaneous exposures produced significantly less potentiation or nearly additive interactions (P = 0.0006 and P <0.0001). The synergism was completely lost under conditions of more prolonged drug exposure (24-h continuous exposure). In conclusion, in this in vitro model of human colon cancer, ZD1694 and SN-38 produced synergistic cytotoxicity. Our findings support the clinical use of this combination and provide a rationale for a clinical trial using sequential short-term exposures to equiactive doses of SN-38 and ZD1694 administered sequentially with a 24-h interval.

AB - The quinazoline folate analogue raltitrexed (ZD1694; Tomudex) and the camptothecin derivative irinotecan are two new agents showing clinical activity against colorectal cancer. To identify the optimal conditions to achieve synergistic cytotoxicity before the clinical development of their combination, we explored the interactions between ZD1694 and the active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38), in vitro. Cytotoxicity was evaluated with a clonogenic assay using the human colon cancer cell line HCT-8. Different schedules of administration and different dose ratios of the two agents were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median- effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). Sequential short-term (1 and 4-h) exposures to SN- 38 followed by ZD1694 resulted in synergistic cytotoxicity at broad dose- effect ranges. At a high level of cell kill, the synergism was greater when either equiactive doses of the two agents or higher relative doses of ZD1694 were used. A 24-h interval between exposure to SN-38 and ZD1694 significantly enhanced the magnitude of the synergy (P = 0.001). The opposite sequence or simultaneous exposures produced significantly less potentiation or nearly additive interactions (P = 0.0006 and P <0.0001). The synergism was completely lost under conditions of more prolonged drug exposure (24-h continuous exposure). In conclusion, in this in vitro model of human colon cancer, ZD1694 and SN-38 produced synergistic cytotoxicity. Our findings support the clinical use of this combination and provide a rationale for a clinical trial using sequential short-term exposures to equiactive doses of SN-38 and ZD1694 administered sequentially with a 24-h interval.

UR - http://www.scopus.com/inward/record.url?scp=0031949701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031949701&partnerID=8YFLogxK

M3 - Article

C2 - 9607593

AN - SCOPUS:0031949701

VL - 4

SP - 1323

EP - 1330

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 5

ER -