Wechselwirkungen zwischen bioaktiven Sekundärmetaboliten und Irinotecan

Klinische Relevanz ◽

Therapeutische Wirksamkeit

ZusammenfassungIrinotecan wird seit mehr als zwei Jahrzehnten in unterschiedlichen Arzneiformen, auch in Kombination mit anderen Arzneistoffen, zur Behandlung einiger Tumorerkrankungen eingesetzt. Irinotecan, ein Prodrug, wird über die Butyrylcholinesterase und über die Carboxylesterasen CES1 und CES2 in die aktive Form SN-38 (7-Ethyl-10-hydroxycamptothecin) verstoffwechselt. SN-38 ist ein starker Topoisomerase-I-Inhibitor. Aufgrund des komplexen Metabolisierungsweges von Irinotecan und wegen der engen therapeutischen Breite des Arzneistoffes ist die klinische Relevanz einer Interaktion zwischen bioaktiven Sekundärmetaboliten und Irinotecan von vielen unterschiedlichen Einflussfaktoren abhängig und kann daher nur im Rahmen einer individualmedizinischen Betreuung Bedeutung haben. Sowohl die Butyrylcholinesterase und die Carboxylesterasen CES1, CES2 als auch CYP3A4, CYP3A5, UGT1A-Isoforme und Transportproteine sind an der Verstoffwechselung und Eliminierung von Irinotecan beteiligt und limitieren die Verfügbarkeit des aktiven Metaboliten SN-38. Inhibition oder Induktion dieser Enzyme durch bioaktive Sekundärmetabolite könnten die therapeutische Wirksamkeit des Irinotecan-Metaboliten SN-38 beeinflussen und für die Ausbildung von Nebenwirkungen ursächlich sein. Der folgende Artikel versucht, einige mögliche Interaktionen abzuschätzen und aufzuzeigen.

Faculty Opinions recommendation of Reversal of established lupus nephritis and prolonged survival of New Zealand black x New Zealand white mice treated with the topoisomerase I inhibitor irinotecan.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2899957.2568055 ◽

2010 ◽

Author(s):

Philipp M Lepper

Keyword(s):

New Zealand ◽

Lupus Nephritis ◽

Topoisomerase I ◽

Prolonged Survival ◽

Faculty Opinions recommendation of Development of a validated immunofluorescence assay for γH2AX as a pharmacodynamic marker of topoisomerase I inhibitor activity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.6316956.6409054 ◽

2010 ◽

Author(s):

John Lazo

Keyword(s):

Topoisomerase I ◽

Immunofluorescence Assay ◽

Inhibitor Activity ◽

Pharmacodynamic Marker

beta-Lapachone, a novel DNA topoisomerase I inhibitor with a mode of action different from camptothecin.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)41552-9 ◽

1993 ◽

Vol 268 (30) ◽

pp. 22463-22468 ◽

Cited By ~ 2

Author(s):

C.J. Li ◽

L Averboukh ◽

A.B. Pardee

Keyword(s):

Mode Of Action ◽

Topoisomerase I ◽

Dna Topoisomerase I ◽

Dna Topoisomerase ◽

Pharmacokinetics, tissue distribution, and metabolism of novel DNA topoisomerase I inhibitor yuanhuacine in rabbit

Xenobiotica ◽

10.1080/00498250802715987 ◽

2009 ◽

Vol 39 (3) ◽

pp. 273-281 ◽

Cited By ~ 4

Author(s):

S. X. Zhang ◽

P. W. Yang ◽

D. C. Zhang ◽

W. Q. Dong ◽

F. H. Zhang ◽

...

Keyword(s):

Tissue Distribution ◽

Topoisomerase I ◽

Dna Topoisomerase I ◽

Dna Topoisomerase ◽

Possible role of edotecarin, a novel topoisomerase I inhibitor, in therapy-related myelodysplastic syndrome

Leukemia & Lymphoma ◽

10.1080/10428190600968350 ◽

2007 ◽

Vol 48 (1) ◽

pp. 192-194 ◽

Cited By ~ 1

Author(s):

Richard D. Carvajal ◽

David H. Ilson ◽

Ariela Noy

Keyword(s):

Myelodysplastic Syndrome ◽

Topoisomerase I ◽

Isodiospyrin as a novel human DNA topoisomerase I inhibitor

Biochemical Pharmacology ◽

10.1016/j.bcp.2003.07.003 ◽

2003 ◽

Vol 66 (10) ◽

pp. 1981-1991 ◽

Cited By ~ 35

Author(s):

Chun-Yuan Ting ◽

Chia-Tse Hsu ◽

Hsiang-Ting Hsu ◽

Jin-Shan Su ◽

Tzong-Yueh Chen ◽

...

Keyword(s):

Topoisomerase I ◽

Dna Topoisomerase I ◽

Dna Topoisomerase ◽

Human Dna ◽

Human Dna Topoisomerase I

Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f ), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies

Annals of Oncology ◽

10.1093/annonc/mdg243 ◽

2003 ◽

Vol 14 (6) ◽

pp. 913-921 ◽

Cited By ~ 8

Author(s):

J.P. Braybrooke ◽

E. Boven ◽

N.P. Bates ◽

R. Ruijter ◽

N. Dobbs ◽

...

Keyword(s):

Phase I ◽

Pharmacokinetic Study ◽

Intravenous Infusion ◽

Topoisomerase I ◽

Solid Malignancies ◽

Exatecan Mesylate

Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2016.08.082 ◽

2016 ◽

Vol 26 (20) ◽

pp. 5069-5072 ◽

Cited By ~ 7

Author(s):

Yusuke Ogitani ◽

Yuki Abe ◽

Takuma Iguchi ◽

Junko Yamaguchi ◽

Tomoko Terauchi ◽

...

Keyword(s):

Topoisomerase I ◽

Drug Conjugation

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1081 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1081-1081

Author(s):

Ashley P Wright ◽

Jodi D Bradley ◽

Timothy Hagerty ◽

Emily A Wyatt

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Cells ◽

Topoisomerase I ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Polymeric Nanoparticle ◽

Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]