TY - JOUR
T1 - NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma
AU - Burton, Jenna H.
AU - Mazcko, Christina
AU - LeBlanc, Amy
AU - Covey, Joseph M.
AU - Ji, Jiuping
AU - Kinders, Robert J.
AU - Parchment, Ralph E.
AU - Khanna, Chand
AU - Paoloni, Melissa
AU - Lana, Sue
AU - Weishaar, Kristen
AU - London, Cheryl
AU - Kisseberth, William
AU - Krick, Erika
AU - Vail, David
AU - Childress, Michael
AU - Bryan, Jeffrey N.
AU - Barber, Lisa
AU - Ehrhart, E. J.
AU - Kent, Michael
AU - Fan, Timothy
AU - Kow, Kelvin
AU - Northup, Nicole
AU - Wilson-Robles, Heather
AU - Tomaszewski, Joseph
AU - Holleran, Julianne L.
AU - Muzzio, Miguel
AU - Eiseman, Julie
AU - Beumer, Jan H.
AU - Doroshow, James H.
AU - Pommier, Yves
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline noncamptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics. Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined. Results: The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; gH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744. Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https:// ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.
AB - Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline noncamptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics. Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined. Results: The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; gH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744. Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https:// ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.
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U2 - 10.1158/1078-0432.CCR-18-1498
DO - 10.1158/1078-0432.CCR-18-1498
M3 - Article
C2 - 30061364
AN - SCOPUS:85056267420
SN - 1078-0432
VL - 24
SP - 5830
EP - 5840
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -