ABSTRACT
We demonstrated that calcitriol has antiproliferative activity in squamous cell carcinoma and prostatic adenocarcinoma and enhances the antitumor activity of platinum-based agents. In this study, we examined whether calcitriol also increases paclitaxel cytotoxicity. The effect of treatment on growth of the murine squamous cell carcinoma (SCCVII/SF) and human prostatic adenocarcinoma (PC-3) was determined by clonogenic assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and monitoring tumor growth. Treatment of SCC or PC-3 cells in vitro with calcitriol prior to paclitaxel significantly reduced clonogenic survival compared with either agent alone. Median-dose effect analysis revealed that calcitriol and paclitaxel interact synergistically. Treatment of SCC or PC-3 tumor-bearing mice with calcitriol prior to paclitaxel resulted in substantially greater growth inhibition than was achieved with either agent alone, supporting the combined use of calcitriol and paclitaxel in the treatment of solid tumors. To explore the molecular basis for the enhanced antitumor activity of this combination, the effect of treatment on p21(Waf-1) (p21), Bcl-2, and poly(ADP-ribose) polymerase expression was evaluated in PC-3. A 72-h pretreatment with calcitriol reduced p21 expression and increased paclitaxel cytotoxicity (measured after 24 h) without evidence of apoptosis [poly(ADP-ribose) polymerase cleavage]. After 48 h, paclitaxel induced apoptosis, the extent of which was increased similarly by pretreatment or concurrent treatment with calcitriol. We therefore propose a model for calcitriol enhancement of paclitaxel cytotoxicity in which the "early" (24 h) effects are schedule dependent and not attributed to enhancement of paclitaxel-induced apoptosis. In contrast, the "delayed" (48-h) enhancement of paclitaxel activity by calcitriol is schedule independent and associated with acceleration of apoptosis.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis , Calcitriol/pharmacology , Paclitaxel/pharmacology , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Calcitriol/therapeutic use , Calcium Channel Agonists/pharmacology , Calcium Channel Agonists/therapeutic use , Cell Survival/drug effects , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/biosynthesis , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Synergism , Gene Expression/drug effects , Mice , Paclitaxel/therapeutic use , Tumor Cells, Cultured , Tumor Stem Cell AssayABSTRACT
1,25-Dihydroxycholecalciferol (1,25-D3) has significant antitumor effects in the murine squamous cell carcinoma (SCC) tumor model in vitro and in vivo. We investigated the basis for this antiproliferative activity and found that, in vitro, 1,25-D3 administration is associated with altered expression of cell cycle regulatory proteins, treatment results in retinoblastoma dephosphorylation, decreased expression of p21(Waf1/Cip1) (p21) mRNA and protein, and increased expression of p27Kip1 (p27) mRNA and protein. Dexamethasone, which acts synergistically with 1,25-D3 to inhibit SCC proliferation, enhanced 1,25-D3-induced down-modulation of p21 without affecting the ability of 1,25-D3 to increase p27 expression. 1,25-D3 did not induce cleavage of poly(ADP-ribose) polymerase. These in vitro data suggest that 1,25-D3 exerts antitumor activity in SCC by perturbing cell cycle progression rather than by inducing apoptosis. In vivo, a 1,25-D3 treatment regimen that results in a decrease in SCC tumor volume is associated with a statistically significant decrease in intratumoral p21 expression. p21 expression is not changed in tumors isolated from control animals or animals treated with a nontherapeutic dose of 1,25-D3. Intratumoral p27 levels were not modulated by 1,25-D3 treatment. Thus, both in vitro and in vivo, 1,25-D3-mediated growth inhibition is associated with p21 down-modulation.
Subject(s)
Antineoplastic Agents/pharmacology , Calcitriol/pharmacology , Cyclins/drug effects , G1 Phase/drug effects , Muscle Proteins , Neoplasm Proteins/drug effects , Resting Phase, Cell Cycle/drug effects , Animals , Apoptosis , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Cell Cycle/drug effects , Cell Division/drug effects , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Dexamethasone/pharmacology , Drug Screening Assays, Antitumor , Female , Mice , Mice, Inbred C3H , Microfilament Proteins/drug effects , Microfilament Proteins/metabolism , Neoplasm Proteins/metabolism , Phosphorylation/drug effects , Retinoblastoma Protein/drug effects , Retinoblastoma Protein/metabolism , Time Factors , Tumor Cells, Cultured/drug effectsABSTRACT
Burnout may develop in highly productive, hard-working individuals from all walks of life. Extending working hours under stressful circumstances may produce a sense of frustration resulting in emotional exhaustion, loss of empathy for patients, and a decreased sense of personal accomplishment. The membership of the American Society of Head and Neck Surgery and the Society of Head and Neck Surgeons was surveyed by mail relative to burnout. A total of 395 head and neck surgeons responded. Mean age was 48 years. The average individual worked an average of 66 hours per week. More than 70% of work was devoted to patient care of which 30% to 50% was devoted to the management of head and neck cancer. A total of 128 (34%) individuals responded that they felt "burned out." Only 27%, however, indicated frustration with disease, whereas 67% indicated frustration by government and 58% indicated frustration by the economics of medical practice. Most respondents enjoy their work, nevertheless, the stress of extending working hours dealing with severely ill patients, and the increased need to deal with government and economic issues is of concern to the community of physicians practicing head and neck surgery. Discussion about and confrontation with these issues are appropriate to facilitate and enhance an individual's ability to continue to function productively in this environment.
