ABSTRACT
Dentists often treat swellings from odontogenic periapical pathologies. One management option involves immediate treatment with antibiotics, followed by surgical intervention. We report a clinical case in which an 8-year-old patient sought care for such a lesion and received pharmacological therapy alone. The lesion expanded into multiple facial spaces approximating the ocular organ and other vital cranial structures. Eventual treatment of the lesion required a CT-scan, followed by an intubated general anesthetic, incision and drainage, extraction of the involved dentition and an overnight hospital admission. This case report is meant to highlight appropriate courses of action in management of rapidly progressing periapical pathologies.
Subject(s)
Periapical Abscess/surgery , Periapical Periodontitis/surgery , Amoxicillin/therapeutic use , Ampicillin/therapeutic use , Anti-Bacterial Agents/therapeutic use , Cellulitis/surgery , Child , Dental Caries/therapy , Disease Progression , Drainage , Face , Female , Humans , Sulbactam/therapeutic use , Tooth ExtractionABSTRACT
Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.
Subject(s)
Apoptosis/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Interferon Regulatory Factors/genetics , Multiple Myeloma/drug therapy , Protein Kinase Inhibitors/pharmacology , Animals , Apoptosis/genetics , Boronic Acids/administration & dosage , Boronic Acids/pharmacology , Bortezomib , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Line, Tumor , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cytotoxins/administration & dosage , Cytotoxins/pharmacology , Down-Regulation/drug effects , Down-Regulation/genetics , Drug Resistance, Neoplasm/drug effects , Drug Synergism , G1 Phase Cell Cycle Checkpoints/genetics , G1 Phase Cell Cycle Checkpoints/physiology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Interferon Regulatory Factors/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Protein Kinase Inhibitors/administration & dosage , Pyrazines/administration & dosage , Pyrazines/pharmacology , Substrate Specificity , Time Factors , Xenograft Model Antitumor AssaysABSTRACT
Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G(1) arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers.
