Cancer is one of the life threatening diseases and the development of novel anticancer molecules is limited by many reasons. In the present investigation, some novel benzo[a]phenazine-5-sulfonic acid derivatives as DNA intercalator was designed with optimized pharmacokinetic features for cancer treatment. The compounds with desired pharmcokinetic profile were synthesized and structurally characterized. Cytotoxic activity study against HL-60 tumor cell lines shows that 10-dimethyl carboxamido derivative of benzo[a]phenazine-5-sulfonic acid is found to be the most active in the series with cytotoxic activity (IC(50) = 19 microM) comparable to cisplatin (IC(50) = 7 microM). The study concluded that the novel benzo[a]phenazine-5-sulfonic acid derivatives were found to have enhanced DNA binding affinity and exhibited significant activity in vitro against HL-60 cell lines. This work will also guide for further development of effective DNA intercalators for cancer treatment. less...

Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic-metabolizing enzyme (XME) involved in the biotransformation of many aromatic and heterocyclic amines. This XME plays key roles in both the detoxification and/or bioactivation of numerous drugs and carcinogens. NAT1 is polymorphic and displays a large tissue distribution. NAT1 activity have been extensively studied because of its potential role in the biotransformation of important carcinogens. Several recent studies suggest that NAT1 may have a role in breast cancer progression. Indeed, this XME has been shown to affect the growth and drug resistance of breast cancer cells and appears as a marker in human estrogen receptor positive breast cancer. In addition, it has been shown that this enzyme is inhibited in vivo by cancer drugs such as cisplatin or tamoxifen. Recent published data suggest that NAT1 could be of therapeutic interest for cancer. We provide here an overview on the putative involvement of NAT1 in cancer and its possible role as a drug target. less...

PURPOSE:: To determine the pattern of failures following intensity modulated radiation therapy for head and neck cancer. MATERIAL AND METHODS:: A retrospective single institution study. Between May 2001 and June 2008, 176 patients with head and neck cancer were treated with intensity modulated radiation therapy at Fox Chase Cancer Center. Ninety-five (54%) were squamous cell carcinoma treated with curative intent. Tumor and nodal stage, tobacco history, definitive versus postoperative therapy (PORT), addition of chemotherapy and RT duration were analyzed for association with patterns of failure. In patients treated with definitive radiation, high-risk PTV (PTV1) was prescribed to 70 Gy and low-risk PTV (PTV2) to 56 Gy. In the PORT setting, PTV1 was prescribed to 60 to 66 Gy and PTV2 to 54 Gy. Patterns of failure were assessed. Local failure (LF) was defined as the persistence of disease or recurrence within PTV1, marginal failure as recurrence at the region of high-dose falloff, and regional failure as nodal recurrence within PTV2. RESULTS:: Median follow-up was 20 months (range: 1-117). Median age was 60 years (range: 28-88), with 80% smokers and 81% stage III or IV. PORT was given to 29% and 71% were treated definitively, with concurrent Cisplatin used in the majority. Three-year local and locoregional (LR) failure rates were 9% and 16%, respectively. Failures occurred in 14 patients: 8 local, 3 regional, 1 LR, and 2 distant. Five of the 8 LF and all 3 marginal failures were observed in PORT cohort. On univariate analysis, the only predictor of LF was the use of PORT (P = 0.06). LR control was 66% for PORT versus 87%, 97% for definitive RT and chemoRT. CONCLUSIONS:: Local, regional failures were more common following PORT related to an increased risk of marginal failures. less...

Telomelysin (OBP-301) is a telomerase-specific replication-component adenovirus. Telomelysin has a human telomerase reverse transcriptase (hTERT) promoter element which efficiently kills human cancer cells, but not normal cells. The present study investigated the correlation between the antitumor effect of telomelysin and mRNA expression of hTERT and coxsackievirus and adenovirus receptor (CAR) in head and neck squamous cell carcinoma (HNSCC) in vitro and whether telomelysin enhances the antitumor effect of paclitaxel or cisplatin, in vivo using a HNSCC xenograft model. We also determined the optimal order for combining telomelysin treatment and chemotherapy as concurrent treatment, telomelysin treatment first and chemotherapy later, chemotherapy first and telomelysin treatment later for achieving the best anticancer effect. The mRNA expression of hTERT and CAR genes was examined by quantitative RT-PCR in 17 HNSCC cell lines. There was no significant correlation between the growth inhibition of telomelysin (ID50 for day 3, 5 and 7) in vitro and mRNA expression levels of hTERT and CAR. Regarding the correlation between CAR expression and telomelysin ID50 for day 3, all cell lines that showed a relative amount of CAR/beta-actin mRNA >0.4 had a low telomelysin ID50. This may indicate that CAR expression contributes to the efficacy of adenovirus infection and the antitumor activity of telomelysin in early stages of treatment. In our in vivo study, combining telomelysin and paclitaxel had an additive effect regardless of treatment order. On the other hand, combining telomelysin and cisplatin had additive effect only when cisplatin treatment preceded telomelysin treatment. These results suggest that paclitaxel is considered innocuous for replication of telomelysin, however cisplatin may influence replication of telomelysin. less...

Purpose/Objectives: To examine the influence of the proposed symptom cluster of fatigue, nausea and vomiting, and sleep disturbances on clinical outcomes defined as behavior changes, depression, and performance status in children and adolescents before and after receiving cisplatin, doxorubicin, or ifosfamide chemotherapy.Design: A prospective, descriptive, within-group, before-and-after-chemotherapy design was used.Setting: Two major childhood cancer treatment hospitals in the United States.Sample: 67 patients aged 7-18 years who were receiving chemotherapy courses of cisplatin, doxorubicin, or ifosfamide.Methods: Fatigue, depression, behavior, and performance assessments were completed on the first day of cisplatin, doxorubicin, or ifosfamide therapy and one week later. Patients wore a wrist actigraph on the nondominant hand during the course of therapy and for 48 hours after discharge from the hospital. Nausea and vomiting were measured every 24 hours during the course of therapy and for 48 hours after discharge. A linear mixed model was used to evaluate the influence of the symptom cluster. Regression analysis was used to examine the associations between performance status and the symptom cluster. Principal component analysis with varimax rotation was used to produce the correlation of sleep symptoms.Main Research Variables: Fatigue, nausea and vomiting, sleep disturbances, behavior, depression, and performance.Findings: Adolescents with the cluster of increased fatigue and sleep disturbances experienced more depressive symptoms and behavior changes. Children with higher levels of fatigue had increased depressive symptoms. The more fatigue parents perceived in their children or adolescents, the more behavior and emotional difficulties were reported.Conclusions: Fatigue, sleep disturbance, and nausea and vomiting, when clustered, impacted depressive symptoms and behavior changes in adolescents after chemotherapy. In children, fatigue alone impacted depressive symptoms and behavior changes.Implications for Nursing: Symptom clusters can have a significant impact on children's and adolescents' quality of life during cancer treatment. Early recognition and intervention for these symptoms are an important nursing role. less...

Gefitinib is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor. The present study was aimed at evaluating the antitumor activity of gefitinib alone or in combination with other antitumor agents. Gefitinib showed higher cytotoxicity against five human tumor cell lines (HSC-2, HSC-3, HSC-4, T98G and U87MG) than against three human normal oral cells (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF). Gefitinib showed little or no growth stimulation effects at lower concentrations (so-called hormetic effect). Non-cytotoxic concentration of gefitinib effectively enhanced the cytotoxicity of docetaxel against HSC-2 and T98G cell, but failed to enhance the cytotoxicity of other antitumor agents (mitoxantrone, doxorubicin, methotrexate, cisplatin, sodium ascorbate, sodium fluoride) or herbal extracts (Drynaria baronii, Angelica sinensis and Cornus officinalis Sieb. et Zucc). Gefitinib alone and combined with docetaxel induced internucleosomal DNA fragmentation and caspase-3 activation in human promyelocytic leukemia HL-60 cells, but not in HSC-2 or T98G cells. Combination treatment with gefitinib and docetaxel induced the formation of acidic organelles (stained with acridine orange) and mitochondrial shrinkage, vacuolization and production of autophagosome and the loss of cell surface microvilli, without destruction of cell surface and nuclear membranes in HSC-2 and T98G cells (demonstrated by transmission electron microscopy), suggesting the induction of autophagy in HSC-2 and T98G cells. less...

BACKGROUND: Docetaxel, ifosfamide and cisplatin have all shown activity in squamous cell carcinoma of the head and neck (SCCHN). The optimal combination of the three drugs is, however, unknown. Considering the favorable results of taxane-containing triplets as induction chemotherapy in locally advanced (LA) SCCHN, DIP (docetaxel, ifosfamide, cisplatin) was studied in this setting as part of a phase I dose- and sequence-exploring study. PATIENTS AND METHODS: D (60 or 75 mg/m(2)) was given by 60-min infusion on day 1, I (1000 mg/m(2)/day), with mesna until 12 hours after I, by 24-h infusion days 1-5, and P (50 or 75 mg/m(2)) by 24-h infusion on days 1 or 5. The cycles were repeated every 21 days. Toxicities according to the National Cancer Institute Common Toxicity Criteria version 2 (NCI-CTC2) were evaluated weekly and response was evaluated every 2 cycles according to the World Health Organization (WHO) criteria. Thereafter, radiotherapy (RT, cumulative dose 70 Gy) or chemoradiation (CRT), both with conventional fractionation, were planned. RESULTS: Twenty-two patients (18 male, 4 female; age 41-66 years, performance status 0-1, 2 T4N0, 3 T3N2, 11 T4N2, 3 T unknown N3, 1 T1N3 and 2 T4N3) received a median of 4 DIP cycles (range 1-5). Grade 4 neutropenia occurred in 18 patients, grade 3 and 4 thrombocytopenia in 5 and 1 patients, respectively, and grade 3 anemia in 5 patients. Gastrointestinal and mucosal toxicities were generally mild/moderate. Vascular complications (probably not DIP-related) precluded local treatment in two patients. Moreover, one patient died on day 13 of the first DIP (neutropenic sepsis and myocardial infarction). The remaining patients received RT (n=2) or CRT (n=17; 16 of these with gemcitabine). The response to 2 x DIP was 95% (1 complete response, 19 partial responses, 1 stable disease); the complete response rate increased to 42% after 4 x DIP. No dose or sequence effect was evident. The minimum follow-up of the surviving patients was 51 months, with median relapse-free survival of 13.8 months and median overall survival of 18.8 months. Only four patients relapsed at distant sites. CONCLUSION: DIP is highly active in previously untreated LA SCCHN, however, toxicity of DIP in this population is substantial. less...

Cisplatin, carboplatin, and oxaliplatin are three FDA-approved members of the platinum anticancer drug family. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses, one of which is the inhibition of transcription. In this report we present (i) a detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry; (ii) research detailing inhibition of cellular transcription by Pt-DNA adducts; and (iii) a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo. A thorough understanding of the molecular mechanism of action of platinum antitumor agents will aid in the development of new compounds in the family. less...

Although cisplatin plays a vital role in the treatment of several types of human cancer, its wide use is limited by the development of drug resistance and associated toxic side effects. Gold and gold complexes have been used to treat a wide range of ailments for many centuries. In recent years, the use of gold(III) complexes as an alternative to cisplatin treatment was proposed due to the similarities of gold and platinum. Gold(III) is isoelectronic with platinum(II) and gold(III) complexes have the same square-planar geometries as platinum(II) complexes, such as cisplatin. Although it was originally thought that gold(III) complexes might have the same molecular target as cisplatin, several lines of data indicated that proteins, rather than DNA, are targeted by gold complexes. We have recently evaluated cytotoxic and anti-cancer effects of several gold(III) dithiocarbamates against human breast cancer cells in vitro and in vivo. We have identified the tumor proteasome as an important target for gold(III) complexes and have shown that proteasome inhibition by gold(III) complexes is associated with apoptosis induction in breast cancer cells in vitro and in vivo. Furthermore, treatment of human breast tumor-bearing nude mice with a gold(III) dithiocarbamate complex was associated with tumor growth inhibition, supporting the significance of its potential development for breast cancer treatment. less...

BACKGROUND: Although triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric cancer has been reported to yield a response rate of about 20%. Because there has been no report of the efficacy of weekly paclitaxel in the third-line setting, this retrospective study investigated the efficacy and toxicities of weekly paclitaxel used in the third-line setting for the treatment of gastric cancer refractory to all three key drugs, fluorouracil, irinotecan, and cisplatin, used in clinical practice. METHODS: In 85 patients with advanced or recurrent histologically confirmed gastric adenocarcinoma who had failed to respond to prior chemotherapy regimens containing fluorouracil, irinotecan, and cisplatin, paclitaxel (80 mg/m(2)) was administered weekly, three times, for 3 weeks out of 4. RESULTS: The median number of courses was 3 (range, 1-38). The overall response rate was 23.2% (19/82) in the patients with measurable lesions, and ascites disappeared in 15 of 48 patients (31.3%). Progression-free survival was 105 days and the median survival time was 201 days from the initiation of paclitaxel administration. Grade 3 or 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 25 (29%), 25 (29%), 37 (44%), and 3 (4%) patients. Other, nonhematological, toxicities were nausea, vomiting, anorexia, sensory neuropathy, fatigue, and febrile neutropenia. CONCLUSION: Weekly paclitaxel administration shows activity against advanced gastric cancer also in the third-line setting. less...