| Reference | 1. Clin Cancer Res. 2015 May 15;21(10):2297-2304. doi:
10.1158/1078-0432.CCR-14-3258. Epub 2015 Mar 5.
<br>
The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through
Species-Specific Insoluble Metabolite Formation.
<br>
Lolkema MP(#)(1)(2), Bohets HH(#)(3), Arkenau HT(1), Lampo A(3), Barale E(3), de
Jonge MJA(2), van Doorn L(2), Hellemans P(3), de Bono JS(1), Eskens FALM(2).
<br>
Author information: <br>
(1)Phase I Unit, Royal Marsden NHS Foundation Trust, Surrey & London, United
Kingdom.
(2)Dept. of medical Oncology, Erasmus MC Cancer Institute Rotterdam, The
Netherlands.
(3)Janssen Research and Development, Beerse, Belgium.
(#)Contributed equally
<br>
PURPOSE: The receptor tyrosine kinase c-Met plays an important role in
tumorigenesis and is a novel target for anticancer treatment. This phase I,
first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and
initial antitumor activity of JNJ-38877605, a potent and selective c-Met
inhibitor.
EXPERIMENTAL DESIGN: We performed a phase I dose-escalation study according to
the standard 3+3 design.<br>
RESULTS: Even at subtherapeutic doses, mild though recurrent renal toxicity was
observed in virtually all patients. Renal toxicity had not been observed in
preclinical studies in rats and dogs. Additional preclinical studies pointed
toward the rabbit as a suitable toxicology model, as the formation of the M10
metabolite of JNJ-38877605 specifically occurred in rabbits and humans.
Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605
induced species-specific renal toxicity. Histopathological evaluation in rabbits
revealed renal crystal formation with degenerative and inflammatory changes.
Identification of the components of these renal crystals revealed M1/3 and M5/6
metabolites. Accordingly, it was found that humans and rabbits showed
significantly increased systemic exposure to these metabolites relative to other
species. These main culprit insoluble metabolites were generated by aldehyde
oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant
probenecid administration in rabbits failed to prevent renal toxicity at dose
levels that could be pharmacologically active.<br>
CONCLUSIONS: Combined clinical and correlative preclinical studies suggest that
renal toxicity of JNJ-38877605 is caused by the formation of species-specific
insoluble metabolites. These observations preclude further clinical development
of JNJ-38877605.
<br>
2. Int J Clin Exp Med. 2015 Apr 15;8(4):6563-7. eCollection 2015.
<br>
Effectiveness of inhibitor rapamycin, saracatinib, linsitinib and JNJ-38877605
against human prostate cancer cells.
<br>
Li W(1), Wang Z(2), Wang L(3), He X(3), Wang G(3), Liu H(3), Guo F(3), Wang Z(4),
Chen G(2).
<br>
Author information: <br>
(1)Department of Urology, Linyi People/’s Hospital Linyi 276000, China ;
Department of Urology, Ninth People/’s Hospital, School of Medicine, Shanghai
Jiaotong University Shanghai 200011, China.
(2)Department of Urology, Jinshan Hospital, Fudan University Shanghai 201508,
China.
(3)Department of Urology, Linyi People/’s Hospital Linyi 276000, China.
(4)Department of Urology, Ninth People/’s Hospital, School of Medicine, Shanghai
Jiaotong University Shanghai 200011, China.
<br>
To investigate the effect of different concentrations of inhibitors rapamycin,
saracatinib, linsitinib and JNJ-38877605 on PC-3 cells with CCK-8 assay,
respectively. PC-3 cells were incubated with different concentrations of
rapamycin, saracatinib, linsitinib and JNJ-38877605, respectively, for 48 h at
37°C, the concentrations of rapamycin were 5 nM, 10 nM, 20 nM, 50 nM, 75 nM, 100
nM; Saracatinib: 0.125 nM, 0.25 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM; Linsitinib: 2 nM,
5 nM, 10 nM, 20 nM, 40 nM, 60 nM; JNJ-38877605: 0.125 nM, 0.5 nM, 1 nM, 2.5 nM, 5
nM, 10 nM. The proliferation of PC-3 cells was examined by CCK-8. Different
concentrations of inhibitor rapamycin remarkably inhibited PC-3 cell
proliferation after 48 h (P<0.05), inhibitory action did not change significantly
from 5 nM-100 nM; different concentrations of saracatinib, linsitinib and
JNJ-38877605 did not inhibit PC-3 cell proliferation after 48 h. Rapamycin
treatment at low concentration can inhibit the proliferation of PC-3 cells, while
saracatinib, linsitinib and JNJ-38877605 do not inhibit PC-3 cell proliferation.
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