ABSTRACT
Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.
Subject(s)
Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasms/metabolism , Pyridinium Compounds/pharmacology , bcl-X Protein/metabolism , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/genetics , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cyclic N-Oxides , Disease Models, Animal , Diterpenes/pharmacology , Drug Resistance, Neoplasm/genetics , Drug Synergism , Epoxy Compounds/pharmacology , Female , Gene Dosage , Humans , Indolizines , Male , Mice , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Neoplasms/genetics , Phenanthrenes/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays , bcl-X Protein/geneticsABSTRACT
Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. Adenosine A(2A) receptor antagonism is a nondopaminergic treatment for PD with clinical and preclinical efficacy. The present studies assessed A(2A) antagonists SCH 412348 and istradefylline in rodent prepulse inhibition (PPI), a model of psychosis. Dopamine receptor agonists pramipexole (0.3-3 mg/kg), pergolide (0.3-3 mg/kg), and apomorphine (0.3-3 mg/kg) significantly disrupted PPI; ropinirole (1-30 mg/kg) had no effect; L-dopa (100-300 mg/kg) disrupted rat but not mouse PPI. SCH 412348 (0.3-3 mg/kg) did not disrupt rodent PPI; istradefylline (0.1-1 mg/kg) marginally disrupted mouse but not rat PPI. These results suggest that A(2A) antagonists, unlike dopamine agonists, have an improved neuropsychiatric side effect profile.
ABSTRACT
BACKGROUND: The scientific potential of animal models of carcinogenesis has not been fully realized because of our limited ability to monitor tumor growth in vivo. OBJECTIVE: To develop an endoscopy-based protocol for the accurate estimation of adenoma size in vivo from images obtained during colonoscopy. DESIGN: To compare estimates of lesion size acquired during endoscopy with those obtained from magnetic resonance imaging (MRI) and at necropsy. SETTING: A small-animal imaging facility. SUBJECTS: Adenomatous polyposis coli multiple intestinal metaplasia Fox Chase Cancer Center mice that develop multiple colorectal adenomas. METHODS: The mice received colonoscopic examination by using a rigid endoscope, and high-resolution images of colon adenomas were captured by using a charge-coupled-device camera. Lesion size was estimated by comparing the dimensions of the adenoma relative to a reference rod by using a novel geometric construction. The resulting areas were compared with estimates from MRIs and validated at necropsy. MAIN OUTCOME MEASUREMENTS: Cross-sectional area of colon adenomas. RESULTS: The cross-sectional area of 20 adenomas was measured in vivo during colonoscopy and compared with the size as measured at necropsy, which yielded a Pearson correlation coefficient of 0.94 (P = 6.52 x 10(-9)). Assessment of interoperator variability, when using measurements from 11 adenomas, yielded a Pearson correlation coefficient of 0.85 (P = 4.35 x 10(-3)) and demonstrated excellent reproducibility. LIMITATIONS: Only the distal colon could be viewed, and endoscopic measurements were 2-dimensional. CONCLUSIONS: An endoscopic method for the reliable measurement of colorectal adenomas in vivo was established. The application of this technique to mouse models of colon carcinogenesis will provide unique insight into the dynamics of adenoma growth.
