Biomedical subjects
Publications and source records attributed to Piyush Kumar.
An old idea for explaining the hierarchy is strong gauge dynamics. We show that such dynamics also stabilizes the moduli in M theory compactifications on manifolds of G2 holonomy without fluxes. This gives stable vacua with softly broken supersymmetry, grand unification, and a distinctive spectrum of TeV and sub-TeV sparticle masses.
OBJECTIVE: To evaluate if pretreatment HPV titers in cancer cervix could predict radiation response and survival outcomes. METHODS: Twenty-one patients of cancer cervix were treated by radiotherapy (RT) alone. HPV titers were estimated using DNA Hybrid Capture II test. Loco-regional response at 1 month of RT--complete or partial response (CR and PR respectively) and survival outcomes--local disease-free (LDFS), disease-free (DFS) and overall (OS) survivals were evaluated against pre- and posttreatment HPV titers. RESULTS: Pretreatment HPV titers ranged from 0.81 to 3966.10 RLU/cut off (mean +/- SD: 1264.39 +/- 1148.22, median: 1129.98). Of the demographic features evaluated, mean HPV titers were significantly different only for patients achieving CR or PR at completion of RT (mean +/- SD for CR vs. PR: 1616.31 +/- 1146.86 vs. 384.57 +/- 538.80, P = 0.022). HPV titers at end of RT ranged from 0.12 to 487.42 RLU/cut off (mean +/- SD: 37.31 +/- 108.60, median: 2.33). Patients with higher pretreatment HPV titers (>1000 RLU/cutoff) had a higher CR (P = 0.022) and better survival compared to those with < or =1000 RLU/cutoff (LDFS, P = 0.004; DFS, P = 0.005; OS, P = 0.012). At completion of RT, those having > or =99.5% fall in HPV had superior survival outcomes than those with <99.5% reduction (LDFS, P = 0.002; DFS, P = 0.002; OS, P = 0.004). CONCLUSIONS: Higher pretreatment HPV titers (>1000 RLU/cutoff) could be considered as a predictor of radiotherapy response and survival in cancer cervix. A reduction in these titers to 99.5% of their baseline values at end of radiotherapy is also associated with better survival outcomes.
OBJECTIVE AND IMPORTANCE: A rare case of aneurysmal bone cyst (ABC) of the temporal bone is presented which, following recurrence after surgery, was successfully treated with radiotherapy. The role of radiotherapy in such cases is reviewed. CLINICAL PRESENTATION: A 30-year-old man presented with a recurrent swelling and pain in right temporal region following surgery for ABC at that site. INTERVENTION: Local radiotherapy to a dose of 31.5 Gy in 18 fractions over 3.5 weeks was delivered to the site of recurrence. The patient had a near total regression of the ABC as evident clinically and on radiological images. CONCLUSION: To the best of our knowledge, radiation for the recurrent ABC at the temporal bone has not been described in the literature. However, in view of the response evident in this patient, radiotherapy seems to be effective for recurrent cases of ABC at the temporal bone and a dose of around 30 to 36 Gy could be effectively delivered with satisfactory results.
INTRODUCTION: 3'-O-(3-Benzenesulfonylfuroxan-4-yl)-5-iodo-2'-deoxyuridine (1) is a cytotoxic nitric oxide (NO) donor-nucleoside dual action prodrug designed to exploit both NO and an antimetabolite nucleoside for cancer therapy. METHODS: 1 was radiolabeled by radioiodide exchange and purified by HPLC in 16% overall radiochemical yield. The specific activity of [(125)I]1 was 31.8 microCi/mug (680 MBq/microM). Protein binding, deiodination, cellular uptake and incorporation of 1 into cellular nucleic acids were measured by standard methods, and its in vivo biodistribution was determined in Balb/c mice bearing implanted EMT-6 tumors following intravenous injection. RESULTS: [(125)I]1 degraded rapidly during the in vitro tests, thus impeding unequivocal assessment but indicating that it was only weakly protein bound and that it was resistant to deiodination under test conditions. Uptake of [(125)I]1 by murine tumor cells (KBALB and KBALB-STK) in vitro was low (approximately 17 fmol/microg protein over 2 h) with only approximately 0.3% (0.04-0.06 fmol/microg protein) of total uptake present in the DNA fraction. In the murine tumor model, liver, kidney, intestine and tumor showed the greatest uptake, with liver, intestine and blood all containing >5 injected dose per gram of tissue (%ID/g) during the 15-min to 2-h postinjection period. Maximum tissue/blood level ratios were 3.6 (2 h) for tumor and 6.4 (24 h) for liver. Low uptake in thyroid and stomach was indicative of minimal in vivo deiodination. CONCLUSIONS: [(125)I]1 undergoes only minimal deoiodination under both in vitro and in vivo conditions. Under conditions of the in vitro NO release assay, 1 reacts to produce a single, major, unstable adduct that decomposes upon workup. Protein binding of [(125)I]1 could not be assessed because of similar chemical reaction with albumin. Incorporation of radioactivity into the cellular nucleic acid fraction was low, and in vivo distribution of [(125)I]1 was consistent with nonspecific reactivity towards tissue nucleophiles. The chemical reactivity of [(125)I]1 mitigates against its use as a NO donor and as a tracer for this class of compounds.
BACKGROUND: The preliminary characterization of [(131)I]iodoazomycin arabinoside ([(131)I]IAZA) as a potential radiotherapeutic radiopharmaceutical is described. METHODS: High-specific-activity [(131)I]IAZA was prepared in therapeutic doses (up to 3 GBq per batch) by isotope exchange in pivalic acid melt and was purified on Sep-Pak cartridges. Stability in 15% ethanol in saline at 4 degrees C was determined by high-performance liquid chromatography. IAZA cytotoxicity (IC(50), approximately 0.1 mM) against both murine (EMT-6) and human (143B, 143B-LTK) tumor cells determined by MTT test was in the range previously reported for EMT-6 cells using a clonogenic assay. Tissue radioactivity levels were measured in a murine tumor model for the 24- to 168-h postinjection period. Radiation dose estimates obtained from the tissue activity levels for this period were calculated from pharmacokinetic (WinNonlin) and dosimetry (MIRD and RAdiation Dose Assessment Resource) parameters. RESULTS: The radioiodination efficiency was >90%, but with systematic losses during Sep-Pak purification, the recovered yields of [(131)I]IAZA were approximately 75%. The product (specific activity, 4.6-6.4 GBq/micromol) was stable for at least 2 weeks, with only approximately 6% degradation over this storage period. Extended biodistribution studies in Balb/c mice bearing implanted EMT-6 tumors showed that the highest tumor/blood radioactivity ratio (T/B; 4.8) occurred 24 h after dosing; the T/B ratio was approximately 1.5 at the end of the 7-day study. The 24- to 168-h tissue radioactivity data fit a one-compartment model except for liver data, which best fit a two-compartment model. Dosimetry estimates showed a tumor self-dose of 7.4 mGy/MBq, which is several-fold higher than for the liver or the kidney. CONCLUSIONS: [(131)I]IAZA can be efficiently radiolabeled at high specific activity, purified by a simple Sep-Pak technique and stored with little radiolysis or chemical decomposition at these specific activities. Based on measured radioactivity burdens during the week following injection and on published animal ([(125)I]IAZA) and clinical ([(123)I]IAZA) dosimetry data, the current dose estimates point to selective tumor irradiation at low dose rates.
1-alpha- and 1-beta-D-Arabinofuranosyl-2-nitroimidazole (alpha-AZA and beta-AZ A) are synthons for a number of potential markers of tissue hypoxia. A one pot synthesis in which 2-nitroimidazole is coupled with a mixture of alpha- and beta-1-O-acetyl-2,3,5-tri-O-benzoyl-D-arabinofuranose in the presence of stannic chloride, followed by deprotection using ammonia/methanol, is described Previously reported conditions for coupling 2-nitroimidazole to 1-alpha-bromoarabinofuranose protected by base-hydrolyzable groups afforded alpha-AZA almost exclusively.
UNLABELLED: The study was performed to compare the (18)F-labeled nitroimidazole compound fluoroazomycin arabinoside ((18)F-FAZA) with the standard hypoxia tracer fluoromisonidazole ((18)F-FMISO) in detection of tumor tissue hypoxia and to verify the oxygenation dependency of (18)F-FAZA uptake. METHODS: Biodistribution of (18)F-FAZA was studied at various time points in EMT6 tumor-bearing BALB/c mice and in AR42J and A431 tumor-bearing nude mice and compared with that of (18)F-FMISO. The presence of tumor tissue hypoxia was verified in 5 EMT6 and 5 AR42J tumors using an oxygen-sensing needle electrode system. To evaluate the oxygenation dependency of (18)F-FAZA uptake, using the Munich prototype animal PET scanner, 2 serial PET scans were performed in 13 A431 tumor-bearing nude mice breathing pure oxygen or room air on 1 d and then selecting the other oxygen breathing condition on the following day. In addition, digital autoradiography was performed with EMT6 tumor-bearing (18)F-FAZA-dosed, nude mice breathing either room air (n = 8) or carbogen (n = 9). RESULTS: Tissue partial pressure of oxygen (Po(2)) electrode measurements revealed that tumor hypoxia was present under room air breathing in EMT6 (tissue Po(2) = 2.9 +/- 2.6) and AR42J tumors (tissue Po(2) = 0.4 +/- 0.2), which was significantly lower compared with that of reference tissue (tissue Po(2) = 25.8 +/- 6.7 and tissue Po(2) = 29.0 +/- 3.0 [mean +/- SD], respectively; P < 0.01). In all tumor models, (18)F-FAZA displayed significantly higher tumor-to-muscle and tumor-to-blood ratios compared with (18)F-FMISO, indicating a faster clearance of (18)F-FAZA from normal tissues. In AR42J tumors, (18)F-FAZA tumor-to-normal ratios were found to increase over time. Serial animal (18)F-FAZA PET studies showed that the tumor-to-background ratio was significantly higher in animals breathing room air compared with that of animals breathing pure oxygen (7.3 +/- 2.3 vs. 4.2 +/- 1.2, respectively; P < 0.001). Similarly, autoradiography showed significantly higher tumor-to-muscle ratios in mice breathing room air compared with those of animals breathing carbogen (5.3 +/- 0.8 vs. 2.2 +/- 0.8; respectively; P < 0.02). CONCLUSION: (18)F-FAZA shows superior biokinetics and is, thus, a promising PET tracer for the visualization of tumor hypoxia. This study also verified a hypoxia-specific uptake mechanism for (18)F-FAZA in murine tumor models.
A series of 5-(trifluoroethoxymethyl)-2',3'-dideoxyuridines and 5-[bis(trifluoroethoxy)-methyl]-2',3'-dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn- and anti conformations for these 5-(2,2,2-trifluoroethoxymethyl)- and 5-[bis(2,2,2-trifluoroethoxy)-methyl]- derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti-HIV-1 and anti-HIV-2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.
BACKGROUND: The Auger electron-emitting agents meta-[125I]iodobenzylguanidine (125I-MIBG) and 123I-MIBG have been proposed as alternatives to 131I-MIBG for the treatment of neuroblastoma, due to the absence of a cross-fire effect which may minimize bone marrow toxicity. However, the differential toxicity of 123I-MIBG towards neuroblastoma cells and cells of haematopoietic lineage has not been studied. OBJECTIVE: To compare the toxic effects of 123I-MIBG on SK-N-SH and SK-N-BE(2) neuroblastoma cells and on cells of haematopoietic lineage, specifically HL-60 human myeloid leukemia cells and bone marrow stem cells (BMSCs) from human adult donors. METHODS: The antiproliferative effects of exchange-labelled or no carrier added (n.c.a.) 123I-MIBG, unlabelled MIBG or the trimethylsilylbenzylguanidine (MTBG) precursor used to prepare n.c.a. 123I-MIBG against SK-N-SH or SK-N-BE(2) cells or HL-60 cells were evaluated using a cell proliferation assay. The toxicity of 123I-MIBG towards SK-N-SH cells or BMSCs from healthy adult human donors was studied using a clonogenic assay. RESULTS: 123I-MIBG was strongly growth inhibitory to SK-N-SH or SK-N-BE(2) cells at concentrations (IC50 185-370 mBq.ml(-1); IC90 740 mBq.ml(-1)) that were sparing to HL-60 cells. Treatment of SK-N-SH cells with 74 mBq of 123I-MIBG decreased colony formation by >90%, whereas colonies from all three populations of stem cells were formed at amounts up to 370 mBq. It was discovered that the MTBG precursor was non-specifically toxic towards both SK-N-SH cells and HL-60 cells, suggesting the need to purify n.c.a. 123I-MIBG for clinical use. CONCLUSION: Our results suggest that 123I-MIBG is a promising novel radiotherapeutic agent for neuroblastoma. For the first time, we report that the MTBG precursor used to prepare n.c.a. 123I-MIBG was toxic towards neuroblastoma cells as well as to HL-60 cells, representing cells of the haematopoietic lineage, suggesting the need for purification.
The present study compares the uptake of [(18)F]Fluoroazomycinarabinofuranoside ((18)FAZA), a recently developed hypoxia tracer for PET imaging of tissue hypoxia, with an established tracer [(18)F]Fluoromisonidazole ((18)FMISO) both in vitro, using Walker 256 rat carcinosarcoma cells, and in vivo in experimental rat tumors eleven to twelve days after tumor cell implantation. In vitro studies indicated that hypoxia-selective uptake of both (18)FAZA and (18)FMISO in tumor cells, 20 and 100 minutes post-incubation was of the same magnitude (20 min: 1.24 +/- 0.4% ((18)FAZA); 1.19 +/- 0.7% ((18)FMISO); 100 min: 3.6 +/- 1.6% ((18)FAZA); 3.3 +/- 1.7% ((18)FMISO)). PET imaging reflected a similar radiotracer distribution in rat tumors for (18)FAZA and (18)FMISO one h after radiotracer injection. The concentration of (18)FAZA in the tumors as measured by PET, however, was lower in comparison to (18)FMISO (SUV(FAZA) = 0.61 +/- 0.2 vs. SUV(FMISO) = 0.92 +/- 0.3, p < 0.05) although the tumor to muscle ratios for (18)FAZA and (18)FMISO did not differ in the PET images that were obtained after one h (SUV(FAZA) = 2.5 +/- 0.5 vs. SUV(FMISO) = 2.9 +/- 0.7). A comparison of PET data three h post-injection (SUV(FAZA) = 3.0 +/- 0.5 vs. SUV(FMISO) = 4.6 +/- 1.8, p < 0.05) demonstrated a lower (18)FAZA uptake that indicates a lower sensitivity of (18)FAZA in comparison to (18)FMISO in detecting hypoxic regions at a longer time in this animal model. However, these data also show a faster elimination of (18)FAZA from blood, viscera and muscle tissue, via the renal system. This advantage of a faster reduction of unspecific binding, in light of similar or marginally lower tumor uptake, warrants further investigation of (18)FAZA as a marker of regional hypoxia in tumors.
The present work describes the synthesis of the beta-isomer of 1-alpha-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (IAZA). Radioiodinated IAZA ((123)I-IAZA) has been extensively studied as a radiopharmaceutical for the diagnosis of regional and/or focal tissue hypoxia in a variety of clinical pathologies. The beta-anomer of IAZA, 1-beta-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (beta-IAZA, 1), was synthesized via an unconventional route starting from 1-beta-D-(ribofuranosyl)-2-nitroimidazole (AZR), with a change of configuration at the C-2'-position to afford 1-beta-D-(arabinofuranosyl)-2-nitroimidazole (beta-AZA, 7). Nucleophilic iodination of the 5'-O-toluenesulfonyl-2',3'-di-O-acetyl precursor of beta-AZA, 9, followed by deprotection, afforded 1 in satisfactory yield. beta-IAZA (1) was also synthesized from 7 using molecular iodine and triphenylphosphine.
Azomycin glucuronate was coupled to a PnAO ligand to create azomycin-based ligands that would form water-soluble 99mTc-azomycin complexes for imaging hypoxic tissue. 1-beta-D-(2-Nitroimidazolyl)glucuronic acid, (see structure in text), was synthesized by coupling 2-nitroimidazole with 1-alpha-bromo-2,3,4-tri-O-acetyl-6-methyl glucuronate, followed by deprotection. Reaction of (see structure in text) with 6-methyl-6-methylamino-HMPnAO (Pn-44) in the presence of BOP reagent in anhydrous dimethyl sulfoxide afforded the PnAO-glucuronides (see structure in text) and (see structure in text). Compound (see structure in text) was isolated in three rotomeric forms. Biological evaluation of (see structure in text) (99mTc-5) indicated selective binding to hypoxic EMT-6 cells, and cytotoxicity to fibroblasts and HeLa, sk24, sk23, and g361 cancer cell lines, at an IC20 <2.5 microgram/ml. In vivo biodistribution of two formulations of (see structure in text) in Balb/c mice with EMT-6 tumor produced diverse results, with one formulation showing no tumor preference, and the other providing a tumor/blood ratio of 2.3 at 4 h post-injection. The latter formulation delineated tumor, large intestine and liver in scintigraphic images.