Intravesical chemotherapy of high-grade bladder cancer with HTI-286, a synthetic analogue of the marine sponge product hemiasterlin.
OBJECTIVE
HTI-286 is a fully synthetic analogue of the natural tripeptide hemiasterlin that inhibits tubulin polymerization and has strong cytotoxic potential. In this study, we evaluate the inhibitory effects of HTI-286 on human bladder cancer growth, both in vitro and as an intravesical agent in an orthotopic murine model.


METHODS
Various bladder cancer cell lines were treated with HTI-286 and mitomycin C (MMC) in vitro. Human KU-7 bladder tumor cells that stably express firefly luciferase were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU-7-luc tumors were given HTI-286 or MMC intravesically twice a week for 2 h. Pharmacokinetic data was obtained using high-performance liquid chromatography-mass spectrometry analyses.


RESULTS
In vitro, HTI-286 was a potent inhibitor of proliferation in all tested cell lines and induced marked increases in apoptosis of KU-7-luc cells even after brief exposure. In vivo, HTI-286 significantly delayed cancer growth of bladder tumors in a dose-dependent fashion. HTI-286, at a concentration of 0.2 mg/mL, had comparable strong cytotoxicity as 2.0 mg/mL of MMC. The estimated systemic bioavailability of intravesically given HTI-286 was 1.5% to 2.1% of the initial dose.


CONCLUSIONS
Intravesical HTI-286 instillation therapy showed promising antitumor activity and minimal toxicity in an orthotopic mouse model of high-grade bladder cancer. These findings provide preclinical proof-of-principle for HTI-286 as an intravesical therapy for nonmuscle-invasive bladder cancer and warrant further evaluation of efficacy and safety in early-phase clinical trials.
Hadaschik
Boris A
BA
The Prostate Centre at Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Adomat
Hans
H
Fazli
Ladan
L
Fradet
Yves
Y
Andersen
Raymond J
RJ
Gleave
Martin E
ME
So
Alan I
AI
D000283:Administration, Intravesical; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D049449:Luminescence; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000627:therapeutic use; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; C473896:HTI-286; D009842:Oligopeptides; D016685:Mitomycin; C467070:hemiasterlin