Carbon nanotubes in cancer theragnosis

Carbon nanotubes as a unique and novel class of nanomaterials have shown considerable promise in cancer therapy and diagnosis amidst the myriad of nanocarriers. The presence of a large surface area enables the engineering of the surface of nanotubes, thus making them biocompatible, and large benefits can be harnessed from them. Together with their ability to encapsulate small molecules, stacking interactions and conjugation, nanotubes have improved the profile of anticancer agents. The propensity to absorb the body transparent NIR radiation also envisages photothermal and photoacoustic therapy using nanotubes. This article sheds light on the role of carbon nanotubes in cancer therapy and diagnosis based on recent findings.     

Particle Shape: A New Design Parameter for Passive Targeting In Splenotropic Drug Delivery

The role of particle size and surface modification on biodistribution of nanocarriers is widely reported. We report for the first time the role of nanoparticle shape on biodistribution. Our study demonstrates that irregular shaped polymer lipid nanoparticles (LIPOMER) evade kupffer cells and localize in the spleen. We also demonstrate the macrophage-evading characteristic of the irregular-shaped LIPOMER. Our results suggest particle shape as an important tool for passive targeting of nanocarriers in splenotropic drug delivery. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2576–2581, 2010     

Synthesis and Antimicrobial Screening of Pyrazolo-3-Aryl Quinazolin-4(3H)ones

2-thio-3-aryl quinazolin-4(3H)one (1) was synthesized by reacting anthranilic acid with thiocarbamate salts of substituted aniline and carbon disulphide, which on reflux with excess of hydrazine hydrate to form 2-hydrazino quinazolin-4(3H)one derivatives (2). The reaction of (2) with variously substituted aryl aldehydes gave the corresponding hydrazones (3). Further, the cyclization of compound (3) in acetic anhydride gave tricyclic pyrazoloquinazolinones (4). All newly synthesized compounds have been tested for their antibacterial activity against gram +ve bacteria B. substilis, S. aureus and gram -ve bacteria E. coli, P. vulgaris. The species used for antifungal activity are Aspergillus niger and Phytophora. Introduction of -OCH3, -OH and -Cl groups to the heterocyclic frame work enhanced antibacterial and antifungal activities.     

Neoplasms associated with germline and somatic NF1 gene mutations

Introduction.

Neurofibromatosis 1 is a tumor predisposition genetic syndrome with autosomal dominant inheritance and virtually 100% penetrance by the age of 5 years. NF1 results from a loss-of-function mutation in the NF1 gene, resulting in decreased levels of neurofibromin in the cell. Neurofibromin is a negative regulator of various intracellular signaling pathways involved in the cellular proliferation. Although the loss of heterozygosity in the NF1 gene may predispose NF1 patients to certain malignancies, additional genetic alterations are a prerequisite for their development. The precise nature of these additional genetic alterations is not well defined, and genetic testing of all malignancies in NF1 patients becomes an essential component of future research in this subset of patients. In addition to germline NF1 mutations, alteration of the somatic NF1 gene is associated with sporadic malignancies such as adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic astrocytoma.

Materials and Methods.

A comprehensive English and non-English language search for all articles pertinent to malignancies associated with NF1 was conducted using PubMed, a search engine provided by the U.S. National Library of Medicine and the National Institutes of Health. Key words searched included the following: “malignancies associated with NF1”, “tumors associated with NF1”, and “NF1 and malignancies”. A comprehensive analysis in terms age and mode of presentation, investigation and therapeutic modalities, and outcome of the published data was performed and compared with similar information on the sporadic cases.

Results.

Malignancies in NF1 patients typically occur at an earlier age and, with an exception of optic pathway gliomas, certain types of malignancies carry a poor prognosis compared with their sporadic counterparts. Malignancies are the leading cause of death in NF1 patients, resulting in a 10- to 15-year decreased life expectancy compared with the general population.

Conclusions.

The lack of well-defined screening tests for early detection and the nonspecific clinical presentation contributes to a poorer outcome in malignancies associated with NF1. Small study group size, mixed patient population, and a lack of uniformity in reporting research results make comparison of treatment outcome for this group difficult. An International Consensus Meeting to address and recommend best practices for screening, diagnosis, management, and follow-up of malignancies associated with NF1 is needed.     

Adjuvant trastuzumab reduces locoregional recurrence in women who receive breast-conservation therapy for lymph node-negative, human epidermal growth factor receptor 2-positive breast cancer

BACKGROUND:

Patients with human epidermal growth factor receptor 2 (HER2)‐positive breast cancer have a higher risk of locoregional recurrence (LRR), even in the setting of early stage, lymph node‐negative disease. In this sequential, retrospective study, the authors evaluated whether adjuvant trastuzumab was associated with reduced LRR in women with lymph node‐negative, HER2‐positive disease who received breast‐conservation therapy (BCT).

METHODS:

By using an institutional database, 197 women were identified who had lymph node‐negative, HER2‐positive breast cancer measuring ≤5 cm diagnosed between 2002 and 2008 and who received BCT, including whole‐breast irradiation. Two cohorts were compared: 70 women who did not receive trastuzumab (the no‐trastuzumab cohort) and 102 women who did receive trastuzumab (the trastuzumab cohort). Kaplan‐Meier methods were used to estimate LRR‐free survival.

RESULTS:

The 2 cohorts were similar in age, tumor size, histology, and hormone receptor status. Chemotherapy was received by 73% of the no‐trastuzumab cohort and by 100% of the trastuzumab cohort. In both groups, 99% of patients completed radiotherapy with a median dose of 60 Gray. The median recurrence‐free follow‐up was 86 months for the no‐trastuzumab cohort and 47 months for the trastuzumab cohort. The 3‐year LRR‐free survival rate was 90% (95% confidence interval, 83%‐97%) for the no‐trastuzumab cohort and 99% (95% confidence interval, 97%‐100%) for the trastuzumab cohort. In the no‐trastuzumab cohort, LRR occurred in 7 patients (median time to LRR, 14 months). In the trastuzumab cohort, there was 1 LRR at 14 months.

CONCLUSIONS:

Even among women with lower risk breast cancer, the relatively high locoregional failure rates associated with positive HER2 status could be reduced markedly with adjuvant trastuzumab chemotherapy. Within 3 years, a 10% LRR rate without trastuzumab and a 1% LRR rate with trastuzumab were observed in women with lymph node‐negative disease who received BCT. Cancer 2012. © 2011 American Cancer Society.     

Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02

BACKGROUND:

The authors conducted exploratory phase 1‐2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3–restricted HER‐2/neu (HER2) peptide, and granulocyte‐macrophage colony‐stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75‐specific cytotoxic T cells. Here, they report 24‐month landmark analyses of disease‐free survival (DFS).

METHODS:

These dose escalation/schedule optimization trials enrolled lymph node‐positive and high‐risk lymph node‐negative patients with HER2 (immunohistochemistry [IHC] 1‐3⁺) expressing tumors. HLA‐A2/A3⁺ patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan‐Meier curves; groups were compared using log‐rank tests.

RESULTS:

Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24‐month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node‐positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+‐2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred.

CONCLUSIONS:

The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node‐positive patients with HER2 low‐expressing tumors is warranted. Cancer 2011. © 2011 American Cancer Society.     

Evaluation of Cissus quadrangularis extracts as an inhibitor of COX, 5-LOX, and proinflammatory mediators

Ethnopharmacological relevance

Cissus quadrangularis is an ancient medicinal plant. It is an active ingredient of one Ayurvedic formula called “Laksha Gogglu”. Its stem is used in food preparation in India. Traditionally it is used to treat various diseases like asthma, indigestion, ear diseases, irregular menstruation, skin diseases, piles, fractured bones, etc.

Aim of the study

This study aimed to evaluate the ability of the plant extracts to inhibit cycloxygenase (COX-1), cycloxygenase (COX-2), and 5-lipoxygenase (5-LOX) enzyme activity. Western blot analysis was also carried out in the quest to determine the effect of active acetone fraction of Cissus quadrangularis (AFCQ) on proinflammatory mediators as acetone extract is found to be the most effective in this study.

Materials and methods

The differential extract of the stem were tested for enzyme inhibition of COX and 5-LOX using spectroscopic and polarigraphic method. Effective acetone extract was partially purified by silica column, one of the active fraction showed dual inhibition against COX and 5-LOX. Western blotting shows downregulation of proinflammatory mediators as well as upregulation of phase-II enzymes.

Results

AFCQ extract showed COX and 5-LOX inhibition with IC₅₀ values of 7 μg/ml, 0.4 μg/ml, and 20 μg/ml for COX-1, COX-2 and 5-LOX respectively. It also showed anti-inflammatory activity on RAW 264.7 cell line with IC₅₀ value 65 μg/ml. In addition to this it is showing inhibition of proinflammatory mediators like iNOS and TNFα, along with translocation of Nrf-2 and upregulation of HO-1.

Conclusion

AFCQ is a COX and 5-LOX inhibitor isolated from the stems of Cissus quadrangularis. It is also effectively downregulate the iNOS, TNFα, and upregulation of HO-1.     

In vitro iontophoretic delivery of nicorandil

The present investigation is aimed at assessing the iontophoretic permeability of nicorandil to evaluate its feasibility for the development of an actively delivered transdermal system. Excised porcine skin was used for permeation study, and steady state flux was optimized with respect to donor concentration, current density, and voltage. Constant current iontophoresis was carried out at 0.3, 0.5, and 0.7 mA/cm(2), whereas constant voltage studies were carried out at 3, 5, and 6.5 V. The effect of donor drug concentration (11.8, 55.8, and 104.8 mg/mL) was studied at the optimized condition of 5 V. An apparent increase in steady state flux was observed in constant current studies, but the increment over the passive diffusion was statistically insignificant (P > 0.05). In contrast, steady state flux was found to be higher than that of passive fluxes when permeation was carried out at 5 and 6.5 V (P < 0.001). Incorporation of alcohol in the donor vehicle increased solubility, but there was a tradeoff in terms of lag time. Conformity with the Nernst-Planck convective transport model suggested that electroosmosis was the dominant mechanism of permeation.     

Examining the pathways linking lower socioeconomic status and advanced melanoma

BACKGROUND.

Low socioeconomic status (SES) is associated with more advanced melanoma at diagnosis and decreased survival. Exploring the pathways linking lower SES and thicker melanoma will help guide public and professional strategies to reduce deaths.

METHODS.

The authors surveyed 566 newly diagnosed patients at Stanford University Medical Center, Veterans Affairs Palo Alto Health Care System, and University of Michigan. SES was assessed by education level (high school/general education degree or less [HS], associate/technical school degree, or ≥college graduate). All data was obtained by self‐report among patients within three months of their diagnosis.

RESULTS.

HS‐educated individuals were significantly more likely than college graduates to believe that melanoma was not very serious (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.79‐4.71) and were less likely to know the asymmetry, borders (irregular), color (variegated), and diameter (>6 mm) (ABCD) melanoma rule or the difference between melanoma and ordinary skin growths (OR, 0.34 [95% CI, 0.23‐0.52] and 0.26 [95% CI, 0.16‐0.41] respectively). Physicians were less likely to have ever told HS‐educated versus college‐educated individuals they were at risk for skin cancer (OR, 0.46; 95% CI, 0.31‐0.71) or instructed them on how to examine their skin for signs of melanoma (OR, 0.40; 95% CI, 0.25‐0.63). HS‐educated individuals were less likely to have received a physician skin examination within the year before diagnosis (OR, 0.54; 95% CI, 0.37‐0.80).

CONCLUSIONS.

Decreased melanoma risk perception and knowledge among low‐SES individuals and decreased physician communication regarding skin examinations of these individuals may be key components of the consistently observed socioeconomic gradient in mortality. The current findings suggest the need to raise melanoma awareness among lower‐SES patients and to increase physician awareness of socioeconomic disparities in clinical communication and care. Cancer 2012. © 2011 American Cancer Society.     

Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-α

Background:

In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis.

Methods:

In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes.

Results:

Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α.

Conclusion:

Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.