High dose rate gynecological applications--radiobiological considerations based on the alpha-beta model.

We compare the relative efficacy of high dose rate (HDR) and low dose rate (LDR) irradiation in gynecological implants, using formulations based on the linear-quadratic (alpha-beta) model. We consider both acute reaction and late effect as endpoints in evaluating equivalence for HDR and LDR treatments, at Point A (as defined in the text) and at other locations. We define a therapeutic factor gamma as an index for relative efficacy, with gamma > 1 indicating a gain in substituting HDR for LDR. It is found that gamma < 1 for most clinical situations, although a modest decrease (of about 15%) in dose to critical organs for HDR would raise gamma above unity.     

Iron oxide nanoparticles for sustained delivery of anticancer agents

We have developed a novel water-dispersible oleic acid (OA)-Pluronic-coated iron oxide magnetic nanoparticle formulation that can be loaded easily with high doses of water-insoluble anticancer agents. Drug partitions into the OA shell surrounding iron oxide nanoparticles, and the Pluronic that anchors at the OA-water interface confers aqueous dispersity to the formulation. Neither the formulation components nor the drug loading affected the magnetic properties of the core iron oxide nanoparticles. Sustained release of the incorporated drug is observed over 2 weeks under in vitro conditions. The nanoparticles further demonstrated sustained intracellular drug retention relative to drug in solution and a dose-dependent antiproliferative effect in breast and prostate cancer cell lines. This nanoparticle formulation can be used as a universal drug carrier system for systemic administration of water-insoluble drugs while simultaneously allowing magnetic targeting and/or imaging.     

Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention

We studied the molecular mechanism of greater efficacy of paclitaxel-loaded nanoparticles (Tx-NPs) following conjugation to transferrin (Tf) ligand in breast cancer cell line. NPs were formulated using biodegradable polymer, poly(lactic-co-glycolide) (PLGA), with encapsulated Tx and conjugated to Tf ligand via an epoxy linker. Tf-conjugated NPs demonstrated greater and sustained antiproliferative activity of the drug in dose- and time-dependent studies compared to that with drug in solution or unconjugated NPs in MCF-7 and MCF-7/Adr cells. The mechanism of greater antiproliferative activity of the drug with conjugated NPs was determined to be due to their greater cellular uptake and reduced exocytosis compared to that of unconjugated NPs, thus leading to higher and sustained intracellular drug levels. The increase in antiproliferative activity of the drug with incubation time in MCF-7/Adr cells with Tf-conjugated NPs suggests that the drug resistance can be overcome by sustaining intracellular drug retention. The intracellular disposition characteristics of Tf-conjugated NPs following their cellular uptake via Tf receptors could have been different from that of unconjugated NPs via nonspecific endocytic pathway, thus influencing the NP uptake, their intracellular retention, and hence the therapeutic efficacy of the encapsulated drug.     

Real Time-PCR HBV-DNA Analysis: Significance and First Experience in Armed Forces

Background

HBV DNA quantitation is used extensively world wide for the diagnosis and monitoring of treatment of Hepatitis B virus (HBV) infection. However, it has still to be popular in India. The aim of this study was to quantitate HBV – DNA by Real time – PCR method in Hepatitis B and in immuno-compromised patients, to compare the results with HBeAg detection and to monitor the response to therapy of chronic Hepatitis B patients to antivirals.

Methods

Ninety one serum samples of Hepatitis group of patients (all HBsAg positive), 41 samples from immuno-compromised patients (all HBsAg negative) and 49 patients of Chronic Hepatitis B group (all HBsAg positive) were the subjects of this first ever study in Armed Forces. Twenty serum samples from healthy volunteers and non-hepatitis B patients served as negative controls. The amplification detection was carried out in a Rotor-Gene 2000-sequence detector

Results

Amongst Hepatitis B group, 33% (30/91) of the samples were positive for HBV-DNA and 26% (24/91) of samples were positive for HBeAg. In the immuno-compromised group of patients 14.6% (6/11) of samples were positive for HIV-DNA and 9.7% (4/41) were positive for HBeAg. Of the Chronic Hepatitis B patients on treatment, all (100%) were positive by HBV-DNA, whereas 29/49 (59.2%) were positive by HBeAg before treatment. After treatment with antivirals, 06/49 (12.2%) were positive by both tests and 11/49 (22.5%) were positive only by HBV-DNA. 32/49 (65.3%) patients became negative serologically after therapy.

Conclusion

HBeAg status did not necessarily reflect HBV-DNA level in the serum, as 10/91 (11%) in the Hepatitis B group, 2/41 (4.9%) in the immuno compromised group and 20/49 (40.8%) patients in the Chronic Hepatitis B group were positive for HBV-DNA but negative for HBeAg. HBV-DNA was not found to be positive amongst any of the negative controls. Real time – PCR is a sensitive and reproducible assay for HBV-DNA quantitation and may be started in Armed Forces referral centers in the near future.Key Words: Real time – PCR, Chronic Hepatitis B, HBV – DNA, Antivirals     

Dose effect for Japanese due to 232Th and 238U in imported drinking water

The consumption rate of bottled mineral water in Japan has increased due to changes in eating habits and contamination of water sources. Radioactivity levels of 238U and 232Th in imported mineral water were checked from the viewpoint of internal radiation for Japanese subjects. Concentration ranges of 238U and 232Th in imported bottled mineral water, domestic bottled mineral water, domestic tap water, and domestic soft drinks were as follows: for U, N.D to 7.48 x 10(3), 1.07 to 344, 0.66 to 104, and 3.04 to 46.2 ng dm (ppt); for Th, 0.60 to 5.12, 0.65 to 22.4, 0.64 to 22.1, and 11.0 to 48.5 ng dm, respectively. In some brands of imported bottled mineral water, U concentration was sometimes much higher than domestic bottled mineral water and domestic tap water. The annual effective dose (1.5 x 10(-3) mSv y(-1) estimated from intake of 238U was approximately 7 times higher than that through dietary intake in Japanese. However, the internal dose added by drinking the imported portable water is negligible compared with total annual internal dose. Concentrations of non-radioactive elements were also compared between imported and domestic bottled water. Geometric means of cobalt, arsenic, strontium, cesium, phosphorous, and calcium in imported bottled water were higher compared with those of domestic bottled mineral water and domestic tap water. Maximum values of 11 elements (arsenic, rubidium, strontium, cesium, barium, sodium, magnesium, potassium, calcium, and manganese) were also found in imported bottled water.     

Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer

Chemotherapy remains the preferred choice of treatment for prostate cancer but modest drug response and significant toxicity by conventional methods of administration limit their efficacy. In our study, we determined the efficacy of paclitaxel (Tx)-loaded biodegradable nanoparticles (NPs) on tumor inhibition. We hypothesized that NPs following conjugation to transferrin (Tf) ligand (NPs-Tf) would enhance the therapeutic efficacy of the encapsulated drug. The antiproliferative activity of NPs was determined in human prostate cancer cell line (PC3) and their effect on tumor inhibition in a murine model of prostate cancer. NPs (approximately 220 nm in diameter, 5.4% w/w drug loading) under in vitro conditions exhibited sustained release of the encapsulated drug (60% release in 60 days). The IC50 (concentration of drug for 50% inhibition of cell growth) of the drug with Tf-conjugated NPs (Tx-NPs-Tf) was about 5-fold lower than that with unconjugated NPs (Tx-NPs) or drug in solution. Animals that received a single-dose intratumoral injection of Tx-NPs-Tf (Tx dose= 4 mg/kg) demonstrated complete tumor regression and greater survival rate than those that received either Tx-NPs or Tx-Cremophor EL formulation. In conclusion, sustained release NPs demonstrated greater antitumor activity following their conjugation to Tf ligand.     

Protective immunity in human lymphatic filariasis: problems and prospects

Human filariasis caused by lymphatic dwelling nematodes, affecting 120 million persons worldwide, is a major public health problem. Efforts towards development of vaccines for such large tissue-dwelling nematodes depends significantly on identification and demonstration of protective immunity in the exposed population. Immunological studies conducted in human filariasis so far are essentially attempts to establish a correlation of the immune response phenotypes with presence or absence of filarial infections/disease in the host, and the cause-effect relationship between the observed immune responses in the host and protective immunity continues to be conjectural. This short review attempts to clarify the functional definition of protective immunity, problems associated with identification of putatively immune subjects in endemic areas, role of antibodies reactive to surface of microfilariae and larvae stages of filarial parasites and importance of undertaking immunological investigations on a longitudinal basis in different cohorts of subjects presenting with one or the features of infection and/or disease for more accurate delineation of protective immunity in human filariasis.     

In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor

High expression of the inducible isoform of heme oxygenase (HO-1) is now well known in solid tumors in humans and experimental animal models. We reported previously that HO-1 may be involved in tumor growth (Tanaka et al., Br. J. Cancer, 88: 902-909, 2003), in that inhibition of HO activity in tumors by using zinc protoporphyrin (ZnPP) significantly reduced tumor growth in a rat model. We demonstrate here that poly(ethylene glycol)-conjugated ZnPP (PEG-ZnPP), a water-soluble derivative of ZnPP, exhibited potent HO inhibitory activity and had an antitumor effect in vivo. In vitro studies with cultured SW480 cells, which express HO-1, showed that PEG-ZnPP induced oxidative stress, and consequently apoptotic death, of these cells. Pharmacokinetic analysis revealed that PEG-ZnPP-administered i.v. had a circulation time in blood that was 40 times longer than that for nonpegylated ZnPP. More important, PEG-ZnPP preferentially accumulated in solid tumor tissue in a murine model. In vivo treatment with PEG-ZnPP (equivalent to 1.5 or 5 mg of ZnPP/kg, i.v., injected daily for 6 days) remarkably suppressed the growth of Sarcoma 180 tumors implanted in the dorsal skin of ddY mice without any apparent side effects. In addition, this PEG-ZnPP treatment produced tumor-selective suppression of HO activity as well as induction of apoptosis. The major reason for tumor-selective targeting of PEG-ZnPP is attributed to the enhanced permeability and retention effect that is observed commonly in solid tumors for biocompatible macromolecular drugs. These findings suggest that tumor-targeted inhibition of HO activity could be achieved by using PEG-ZnPP, which induces apoptosis in solid tumors, probably through increased oxidative stress.