EO9

A novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models

H. R. Hendriks, P. E. Pizao, D. P. Berger, K. L. Kooistra, M. C. Bibby, E. Boven, H. C. Dreef-van der Meulen, R. E C Henrar, H. H. Fiebig, J. A. Double, H. W. Hornstra, H. M. Pinedo, P. Workman, G. Schwartsmann

Research output: Contribution to journalArticle

Abstract

EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, E09 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, E09 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared to leukaemia cell lines both in the Corbett two-tumour assay and in the disease-oriented human tumour cell line panel of the U.S. National Cancer Institute. In the latter system activity was particularly apparent in colon, melanoma and central nervous system lines, together with some renal and non-small cell lung lines. Preferential cytotoxicity towards hypoxic versus aerobic EMT6 mouse mammary tumour cells was observed. In vivo, EO9 was inactive against the P388 murine leukaemia, while exerting significant antiproliferative effects against several murine and human solid tumours, including the generally resistant MAC mouse colon tumours and gastric, ovarian and breast xenografts. These results confirmed in vitro observations of preferential solid tumour activity. In animal toxicology studies, E09 induced vascular congestion in the gastrointestinal tract, but no significant bone marrow toxicity. The ld10 value of E09 after a single intravenous injection into mice was 9 mg/kg (27 mg/m2). A dose of one-tenth of the mouse equivalent ld10 (2.7 mg/m2), the recommended starting dose for clinical phase I studies, was found to be safe in rats. Considering its distinct mechanism of bioactivation as compared to mitomycin C, its preferential solid tumour activity, its excellent activity against hypoxic cells, and lack of significant bone marrow toxicity in animal studies, E09 has been selected for clinical evaluation within the framework of the EORTC.

Original languageEnglish (US)
Pages (from-to)897-906
Number of pages10
JournalEuropean Journal of Cancer
Volume29
Issue number6
DOIs
StatePublished - 1993
Externally publishedYes

Fingerprint

apaziquone
Indolequinones
Bone Marrow
Neoplasms
Mitomycin
Colon
Leukemia P388
Cell Line
National Cancer Institute (U.S.)
Tumor Cell Line
Heterografts
Intravenous Injections
Toxicology
Blood Vessels
Gastrointestinal Tract
Melanoma
Stomach
Leukemia
Breast
Central Nervous System

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Hematology

Cite this

EO9 : A novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models. / Hendriks, H. R.; Pizao, P. E.; Berger, D. P.; Kooistra, K. L.; Bibby, M. C.; Boven, E.; Dreef-van der Meulen, H. C.; Henrar, R. E C; Fiebig, H. H.; Double, J. A.; Hornstra, H. W.; Pinedo, H. M.; Workman, P.; Schwartsmann, G.

In: European Journal of Cancer, Vol. 29, No. 6, 1993, p. 897-906.

Research output: Contribution to journalArticle

Hendriks, HR, Pizao, PE, Berger, DP, Kooistra, KL, Bibby, MC, Boven, E, Dreef-van der Meulen, HC, Henrar, REC, Fiebig, HH, Double, JA, Hornstra, HW, Pinedo, HM, Workman, P & Schwartsmann, G 1993, 'EO9: A novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models', European Journal of Cancer, vol. 29, no. 6, pp. 897-906. https://doi.org/10.1016/S0959-8049(05)80434-4
Hendriks, H. R. ; Pizao, P. E. ; Berger, D. P. ; Kooistra, K. L. ; Bibby, M. C. ; Boven, E. ; Dreef-van der Meulen, H. C. ; Henrar, R. E C ; Fiebig, H. H. ; Double, J. A. ; Hornstra, H. W. ; Pinedo, H. M. ; Workman, P. ; Schwartsmann, G. / EO9 : A novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models. In: European Journal of Cancer. 1993 ; Vol. 29, No. 6. pp. 897-906.
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T2 - A novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models

AU - Hendriks, H. R.

AU - Pizao, P. E.

AU - Berger, D. P.

AU - Kooistra, K. L.

AU - Bibby, M. C.

AU - Boven, E.

AU - Dreef-van der Meulen, H. C.

AU - Henrar, R. E C

AU - Fiebig, H. H.

AU - Double, J. A.

AU - Hornstra, H. W.

AU - Pinedo, H. M.

AU - Workman, P.

AU - Schwartsmann, G.

PY - 1993

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N2 - EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, E09 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, E09 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared to leukaemia cell lines both in the Corbett two-tumour assay and in the disease-oriented human tumour cell line panel of the U.S. National Cancer Institute. In the latter system activity was particularly apparent in colon, melanoma and central nervous system lines, together with some renal and non-small cell lung lines. Preferential cytotoxicity towards hypoxic versus aerobic EMT6 mouse mammary tumour cells was observed. In vivo, EO9 was inactive against the P388 murine leukaemia, while exerting significant antiproliferative effects against several murine and human solid tumours, including the generally resistant MAC mouse colon tumours and gastric, ovarian and breast xenografts. These results confirmed in vitro observations of preferential solid tumour activity. In animal toxicology studies, E09 induced vascular congestion in the gastrointestinal tract, but no significant bone marrow toxicity. The ld10 value of E09 after a single intravenous injection into mice was 9 mg/kg (27 mg/m2). A dose of one-tenth of the mouse equivalent ld10 (2.7 mg/m2), the recommended starting dose for clinical phase I studies, was found to be safe in rats. Considering its distinct mechanism of bioactivation as compared to mitomycin C, its preferential solid tumour activity, its excellent activity against hypoxic cells, and lack of significant bone marrow toxicity in animal studies, E09 has been selected for clinical evaluation within the framework of the EORTC.

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