Metformin as an Alternative Radiosensitizing Agent to 5-Fluorouracil During Neoadjuvant Treatment for Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiation for locally advanced rectal cancer combining 5-fluorouracil with radiation increases tumor regression compared with radiation alone. However, it occurs at the cost of significant treatment-related toxicity. Patients with rectal cancer using metformin have been associated with improved response to radiotherapy. OBJECTIVE: The purpose of this study was to evaluate the radiosensitizing effects of metformin in vitro and in vivo and compare it with a standard combination of radiation/5-fluorouracil. DESIGN: Colorectal cancer cell lines SW480, HT29, and HCT116 were used as models. Cell viability was compared under treatments with radiation, radiation/5-fluorouracil, metformin, radiation/metformin, and radiation/5-fluorouracil/metformin. Nude mice were injected subcutaneously with SW480 cells and treated for 1 week with radiation/5-fluorouracil, metformin, radiation/metformin, or radiation/5-fluorouracil/metformin. Tumor volume was evaluated for 4 weeks after treatment completion. The phosphorylation status of key proteins of the PI3K/Akt/mTOR pathway was determined by immunoblots. SETTINGS: This was an experimental study conducted in vitro and in vivo. PATIENTS: Animal models/cell lines were used. MAIN OUTCOME MEASURES: The end point was to investigate how metformin compares with 5-fluorouracil as a radiosensitizer. RESULTS: All cell lines significantly decreased cell viability after treatment with radiation/metformin when compared with radiation alone. Radiation/metformin was superior to radiation/5-fluorouracil in SW480 (37% vs 74%; p < 0.001). In HT29 and in HCT116, radiation/metformin was inferior to radiation/5-fluorouracil (40.0% vs 13.8%, p < 0.001 and 40.0% vs 7.0%, p < 0.001), mainly because of increased 5-fluorouracil toxicity (≤20% of cell viability). In vivo assays indicated that radiation/metformin treatment was comparable with radiation/5-fluorouracil (557 vs 398 mm; p > 0.05) and that the addition of metformin to the standard radiation/5-fluorouracil did not improve tumor response (349 mm; p > 0.05). Metformin exerted strong PI3K/Akt/mTOR pathway inactivation effects after 24-hour exposure (increasing pAMPK, p < 0.01; decreasing pAkt, p < 0.01; and pS6, p <0.05). LIMITATIONS: In vitro and in vivo chemoradiation regimens cannot be directly translated to human delivery methods. CONCLUSIONS: Metformin enhances tumor response to radiation in vitro and in vivo. Metformin is an attractive alternative radiosensitizing agent to be considered in future studies/trials. See Video Abstract at http://links.lww.com/DCR/B219. LA METFORMINA COMO AGENTE RADIOSENSIBILIZADOR ALTERNATIVO A 5FU DURANTE EL TRATAMIENTO NEOADYUVANTE PARA CÁNCER DE RECTO: La quimiorradiación neoadyuvante para el cáncer de recto localmente avanzado que combina 5FU con radiación aumenta la regresión tumoral en comparación con la radiación sola. Sin embargo, se produce a costa de una toxicidad significativa relacionada con el tratamiento. Los pacientes con cáncer de recto que usan metformina se han asociado con una mejor respuesta a la radioterapia.Evaluar los efectos radiosensibilizantes de metformina in vitro e in vivo y compararlo con la combinación estándar de radiación / 5FU.Se usaron como modelos las líneas celulares de cáncer colorrectal SW480, HT29 y HCT116. La viabilidad celular se comparó en tratamientos con radiación, radiación / 5FU, metformina, radiación / metformina y radiación / 5FU / metformina. A los ratones desnudos se les inyectó por vía subcutánea células SW480 y fueron tratados durante una semana con radiación / 5FU, metformina, radiación / metformina o radiación / 5FU / metformina. El volumen tumoral se evaluó durante 4 semanas después de la finalización del tratamiento. El estado de fosforilación de las proteínas clave de la vía PI3K / Akt / mTOR se determinó mediante inmunotransferencias.Estudio experimental in vitro e in vivo.Modelo animal / líneas celulares.El punto final fue investigar cómo la metformina se compara con 5FU como un radiosensibilizador.Todas las líneas celulares disminuyeron significativamente la viabilidad celular después del tratamiento con radiación / metformina en comparación con la radiación sola. La radiación / metformina fue superior a la radiación / 5FU en SW480 (37% frente a 74%; p <0,001). En el HT29 y el HCT116 la radiación / metformina fue inferior a la radiación / 5FU (40% vs 13.8%, p <0.001 y 40% vs 7%, p <0.001; respectivamente), debido principalmente al aumento de la toxicidad de 5FU (≤20% de la célula viabilidad). Los ensayos in vivo indicaron que el tratamiento con radiación / metformina era comparable a la radiación / 5FU (557 vs 398 mm, p > 0.05), y que la adición de metformina a la radiación estándar / 5FU no mejoró la respuesta tumoral (349 mm, p > 0.05). La metformina ejerció fuertes efectos de inactivación de la vía PI3K / Akt / mTOR después de 24 horas de exposición (aumentando pAMPK p < 0.01, disminuyendo pAkt, p < 0.01; y pS6, p < 0.05).Los regímenes de CRT in vitro e in vivo no se pueden traducir directamente a los métodos de entrega en humanos.La metformina mejora la respuesta tumoral a la radiación in vitro e in vivo. La metformina es un agente alternativo de radiosensibilización atractivo para ser considerado en futuros estudios / ensayos. Consulte Video Resumen en http://links.lww.com/DCR/B219. (Traducción-Dr Gonzalo Hagerman).

Pharmacodynamics of current and emerging treatments for cervical cancer.

Introduction: Beyond early stages of cervical cancer (1A1, IA2, IB1, IIA1,), locally advanced disease (IB2, IIA2, IIA2, IIB, IIIA, IIIB, IIIC, IVA) and advanced (metastatic, recurrent or persistent disease) patients require drug therapy either as radiosensitizer, adjuvant or as palliative systemic chemotherapy. Areas covered: This review briefly discusses the achievements in treating cervical cancer. Expert opinion: Two studies are ongoing to optimize treatment after radical hysterectomy. These studies compare chemoradiation versus radiation in intermediate-risk patients or increasing treatment intensity (chemoradiation plus adjuvant chemotherapy versus chemoradiation) for high-risk and locally advanced cervical cancer. Concerning advanced disease, bevacizumab increased median survival for only 3.5 months when added to a cisplatin-doublet. Although this increase is slightly superior to the 2.9 months gained with cisplatin topotecan versus cisplatin, (0.6 months of difference), the doublet plus bevacizumab is considered the standard of care. Recently, pembrolizumab became an alternative for advanced disease that progresses to first-line treatment. Beyond that, the number of phase II and phase III trials in advanced disease is limited but on the increase. HPV E6/E7 oncoproteins are the Achilles Heel of cervical cancer, and there is cautious optimism that antagonists of these oncoproteins will be further developed.

In vivo Characterization of the Radiosensitizing Effect of a Very Low Dose of BrdU in Murine Cells Exposed to Low-Dose Radiation.

The aim of the present study was to characterize the in vivo radiosensitizing effect of a very low dose of bromodeoxyuridine (BrdU) in mice exposed to low-dose radiation by establishing the following: (1) the radiosensitizing effect during DNA synthesis using single-cell gel electrophoresis (SCGE) in murine bone marrow cells, and (2) the number and timing of the mechanisms of genotoxicity and cytotoxicity, as well as the correlation of both end points, using flow cytometry analysis of the kinetics of micronucleus induction in reticulocytes. Groups of mice received intraperitoneal injections of 0.125 mg/g of BrdU 24 h prior to irradiation with 0.5 Gy of 60 Co gamma rays. DNA breaks measured using SCGE were determined at 30 min after exposure to radiation. The kinetics of micronucleated reticulocyte (MN-RET) induction was determined every 8 h after irradiation up to 72 h. The results from both experimental models indicated that low-level BrdU incorporation into DNA increased the sensitivity to 0.5 Gy of radiation, particularly in the S phase. The formation of micronuclei by gamma rays was produced at three different times using two main mechanisms. In the BrdU-substituted cells, the second mechanism was associated with a high cytotoxic effect that was absent in the irradiated BrdU-unsubstituted cells. The third mechanism, in which micronucleus formation was increased in irradiated substituted cells compared with the irradiated nonsubstituted control cells, was also related to an increase in cytotoxicity. Environ. Mol. Mutagen. 60:534-545, 2019. © 2019 Wiley Periodicals, Inc.

Cisplatin Every 3 Weeks Versus Weekly With Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck.

BACKGROUND: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches. METHODS: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression. RESULTS: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss. CONCLUSION: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS.

Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial.

BACKGROUND: C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib. METHODS: Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437. RESULTS: Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients. CONCLUSIONS: A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.

Improvement of the boron neutron capture therapy (BNCT) by the previous administration of the histone deacetylase inhibitor sodium butyrate for the treatment of thyroid carcinoma.

We have shown that boron neutron capture therapy (BNCT) could be an alternative for the treatment of poorly differentiated thyroid carcinoma (PDTC). Histone deacetylase inhibitors (HDACI) like sodium butyrate (NaB) cause hyperacetylation of histone proteins and show capacity to increase the gamma irradiation effect. The purpose of these studies was to investigate the use of the NaB as a radiosensitizer of the BNCT for PDTC. Follicular thyroid carcinoma cells (WRO) and rat thyroid epithelial cells (FRTL-5) were incubated with 1 mM NaB and then treated with boronophenylalanine ¹°BPA (10 µg ¹°B ml⁻¹) + neutrons, or with 2, 4-bis (α,ß-dihydroxyethyl)-deutero-porphyrin IX ¹°BOPP (10 µg ¹°B ml⁻¹) + neutrons, or with a neutron beam alone. The cells were irradiated in the thermal column facility of the RA-3 reactor (flux = (1.0 ± 0.1) × 10¹° n cm⁻² s⁻¹). Cell survival decreased as a function of the physical absorbed dose in both cell lines. Moreover, the addition of NaB decreased cell survival (p < 0.05) in WRO cells incubated with both boron compounds. NaB increased the percentage of necrotic and apoptotic cells in both BNCT groups (p < 0.05). An accumulation of cells in G2/M phase at 24 h was observed for all the irradiated groups and the addition of NaB increased this percentage. Biodistribution studies of BPA (350 mg kg⁻¹ body weight) 24 h after NaB injection were performed. The in vivo studies showed that NaB treatment increases the amount of boron in the tumor at 2-h post-BPA injection (p < 0.01). We conclude that NaB could be used as a radiosensitizer for the treatment of thyroid carcinoma by BNCT.

Carnosol, radiation and melanoma: a translational possibility.

PURPOSE: To compare the genoprotective and radioprotective effect of carnosol (COL) against damage induced by ionizing radiation with similar effects produced by different antioxidant compounds. METHODS: The genoprotective effect was studied by means of the micronucleus test for antimutagenic activity in which the reduction in the frequency of micronuclei was evaluated in cytokinesis-blocked cells of human lymphocytes. The radioprotective effects were studied by cell viability test (MTT) in PNT2 (normal prostate) and B16F10 (melanoma) cell lines when they were administered before exposure to different X-ray doses (4, 6, 8, 10 and 0 Gy). RESULTS: Carnosol shows a significant genoprotective capacity (p < 0.001) against radiation with a protection factor of 50 %, and a dose-reduction factor of 4.3. Cell survival obtained with COL administered before exposure to 10 Gy of X-rays showed a protection factor of 55.1 %, eliminating 39 % of radiation-induced cell death in normal epithelial cells of prostate (PNT2) (p < 0.001). However, in the melanoma cell lines (B16F10) assayed, COL acted not as a radioprotector, but as a sensitizing agent increasing the cellular death by 34 % (p < 0.01) and producing an enhancement ratio of 2.12. CONCLUSIONS: Carnosol may be developed as a radioprotective agent in the non-tumoral cells. However, in the B10F16 melanoma cells, melanogenesis is activated by COL leading to redistribution of the enzymatic balances of glutathione and cysteine-lyase production, which could compromise the intracellular redox defence system. This effect appears as an increase in the capacity of ionizing radiation-induced damage, and thus exhibits a paradoxical protective effect of COL on melanoma cells.

Preliminary clinical study of weekly recombinant human endostatin as a hypoxic tumour cell radiosensitiser combined with radiotherapy in the treatment of NSCLC.

OBJECTIVE: To investigate the clinical effects and adverse effects of weekly recombinant human endostatin (RHES) as a hypoxic tumour cell radiosensitiser combined with radiotherapy in the treatment of non-small-cell lung cancer (NSCLC). METHODS: Fifty hypoxia-positive cases of pathology-diagnosed NSCLC (stage I-III) were randomly divided into a RHES+radiotherapy group (25 cases) and a radiotherapy alone group (25 cases). Intensity-modulated radiotherapy (IMRT) with a total dose of 60 Gy/30F/6W was adopted in the two groups. Target area included primary foci and metastatic lymph nodes. In the RHES+radiotherapy group, RHES (15 mg/day) was intravenously given during the first week. The therapeutic effects and adverse reactions were evaluated after treatment. RESULTS: In the RHES+radiotherapy and radiotherapy alone groups, the total effective rates (CR+PR) were 80% and 44% (χ(2)=6.87, p=0.009), respectively. The one-year and two-year local control rates were (78.9±8.4)% and (68.1±7.8)% (p=0.027), and (63.6±7.2)% and (43.4±5.7)% (p=0.022), respectively. The median progression-free survival was (21.1±0.97) and (16.5±0.95) months, respectively. The one-year and two-year overall survival rates were (83.3±7.2)% and (76.6±9.3)% (p=0.247), and (46.3±2.4)% and (37.6±9.1)% (p=0.218), respectively. CONCLUSION: RHES combined with radiotherapy within the first week has better short-term therapeutic effects and local control rate, and no severe adverse reactions in treatment of NSCLC. However, it failed to significantly improve the one-year and two-year overall survival rates.

Pharmacokinetic evaluation of gemcitabine hydrochloride for the treatment of cervical cancer.

INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.

Weekly gemcitabine and cisplatin in combination with radiotherapy in patients with locally advanced head-and-neck cancer: Phase I study.

PURPOSE: To define the maximum tolerated dose by describing the dose-limiting toxicity (DLT) of weekly gemcitabine and cisplatin in patients with locally advanced head-and-neck (LAHN) cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with LAHN cancer were enrolled in a prospective, dose-escalation Phase I study. Toxicity was graded according to the Common Toxicity Criteria score. Maximum tolerated dose was defined when DLT developed in 2 of 6 patients. The starting dose of cisplatin was 20 mg/m(2) and that of gemcitabine was 10 mg/m(2) in 3 patients, with a subsequent dose escalation of 10 mg/m(2) of cisplatin only for 3 new patients. In the next levels, only a dose escalation of gemcitabine with 10 mg/m(2) for each new cohort was used (Level 1, 10 mg/m(2) of gemcitabine and 20 mg/m(2) of cisplatin; Level 2, 10 mg/m(2) of gemcitabine and 30 mg/m(2) of cisplatin; and Level 3, 20 mg/m(2) of gemcitabine and 30 mg/m(2) of cisplatin). Radiation therapy was administered by use of a conformal technique over a period of 6 to 7 weeks in 2.0-Gy daily fractions for 5 consecutive days per week to a total dose of 70 Gy. RESULTS: From 2008 to 2009, 12 patients completing 3 dose levels were included in the study. At Dose Level 3, 1 of 3 patients had DLT with Grade 3 mucositis. Of the next 3 required patients, 2 showed DLT with Grade 3 dermatitis. At a follow-up of 3 months, 10 of 12 evaluable patients (83.3%) obtained a complete response and 1 patient (8.3%) obtained a partial response. Among the complete responders, at a median follow-up of 10 months (range, 6-14 months), 9 patients are alive and disease free. CONCLUSION: Gemcitabine at low doses combined with cisplatin is a potent radiosensitizer effective in patients with LAHN cancer. The recommended Phase II dose is 10 mg/m(2) of gemcitabine and 30 mg/m(2) of cisplatin with an acceptable tolerability profile.

High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin.

INTRODUCTION: The combination of chemotherapy and thoracic radiation is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). However, most favorable chemotherapy regimen, timing of full-dose chemotherapy, and optimal combination of chemotherapy with radiation remain to be determined. Our primary objective was to evaluate the efficacy and safety of gemcitabine concurrent with radiotherapy after induction chemotherapy with gemcitabine plus carboplatin for locally advanced NSCLC. PATIENTS AND METHODS: Patients with histologically proven NSCLC stage IIIA and -B received carboplatin (area under the curve of 2.5) and gemcitabine (800 mg/m) on days 1 and 8, every 21 days for two cycles, followed by conventional fractioned thoracic radiotherapy and concomitant weekly gemcitabine 200 mg/m, and finally, consolidation chemotherapy. RESULTS: Inclusion was discontinued because of high-grade 3 to 5 radiation-pneumonitis events (6 of 19 patients, 31.6%), including one treatment-related death associated with radiation pneumonitis. Median follow-up was 11.9 months. Most common grades 3/4 hematological side effects comprised anemia, neutropenia 3 of 19 patients, each (15.8%), and thrombocytopenia (4 of 19, 21.1%) during induction. Partial response was observed in 10 patients (52.6%) following induction chemotherapy. After concurrent chemo-radiotherapy, overall response was 68.4%. Four patients (21.1%) underwent surgical resection. Median progression-free survival and overall survival were 12 +/- 1 month (95% confidence interval [CI], 9.8-14.1) and 21 +/- 3.5 months (95% CI, 14-27.9 months), respectively. CONCLUSION: Concurrent radiotherapy with gemcitabine after induction with gemcitabine and carboplatin showed a high-response rate; however, it is associated with excessive pulmonary toxicity. Adjustments in gemcitabine dosage during radiotherapy or changes in radiotherapy planning could reduce toxicity.

Boron biodistribution study in colorectal liver metastases patients in Argentina.

Ex-situ BNCT for multifocal unresectable liver metastases employing whole or partial autograft techniques requires knowledge of boron concentrations in healthy liver and metastases following perfusion and immersion in Wisconsin solution (W), the procedure employed for organ preservation during ex-situ irradiation. Measurements of boron concentration in blood, liver and metastases following an intravenous infusion of BPA-F in five colorectal liver metastases patients scheduled for surgery were performed. Tissue samples were evaluated for boron content pre and post perfusion and immersion in W. Complementary histological studies were performed. The data showed a dose-dependent BPA uptake in liver, a boron concentration ratio liver/blood close to 1 and a wide spread in the metastases/liver concentration ratios in the range 0.8-3.6, partially attributable to histological variations between samples. Based on the boron concentrations and dose considerations (liver < or =15 Gy-Eq and tumor> or =40 Gy-Eq) at the RA-3 thermal neutron facility (mean flux of about (6+/-1) x 10(9) n cm(-2)s(-1)), ex-situ treatment of liver metastases at RA-3 would be feasible.

Photodynamic ultradeformable liposomes: Design and characterization.

Hydrophobic ([tetrakis(2,4-dimetil-3-pentyloxi)-phthalocyaninate]zinc(II)) (ZnPc) and hydrophilic ([tetrakis(N,N,N-trimethylammoniumetoxi)-phthalocyaninate]zinc(II) tetraiodide) (ZnPcMet) phthalocyanines were synthesized and loaded in ultradeformable liposomes (UDL) of soybean phosphatidylcholine and sodium cholate (6:1, w/w, ratio), resulting 100 nm mean size vesicles of negative Zeta potential, with encapsulation efficiencies of 85 and 53%, enthalpy of phase transition of 5.33 and 158 J/mmol for ZnPc and ZnPcMet, respectively, indicating their deep and moderate partition into UD matrices. Matrix elasticity of UDL-phthalocyanines resulted 28-fold greater than that of non-UDL, leaking only 25% of its inner aqueous content after passage through a nanoporous barrier versus 100% leakage for non-UDL. UDL-ZnPc made ZnPc soluble in aqueous buffer while kept the monomeric state, rendering singlet oxygen quantum yield (Phi(Delta)) similar to that obtained in ethanol (0.61), whereas UDL-ZnPcMet had a four-fold higher Phi(Delta) than that of free ZnPcMet (0.21). Free phthalocyanines were non-toxic at 1 and 10 microM, both in dark or upon irradiation at 15 J/cm2 on Vero and J-774 cells (MTT assay). Only liposomal ZnPc at 10 microM was toxic for J-774 cells under both conditions. Additionally, endo-lysosomal confinement of the HPTS dye was kept after irradiation at 15 J/cm2 in the presence of UDL-phtalocyanines. This could lead to improve effects of singlet oxygen against intra-vesicular pathogen targets inside the endo-lysosomal system.

Chemoradiation with gemcitabine for cervical cancer in patients with renal failure.

The prognosis of cervical cancer patients with renal failure secondary to obstructive uropathy is poor. Our objective was to analyze our experience in the management with chemoradiation of untreated cervical cancer patients complicated by obstructive nephropathy and kidney dysfunction. Untreated patients with cervical cancer and renal failure as manifested by raised serum creatinine were treated with pelvic radiotherapy concurrently with weekly gemcitabine at 300 mg/m2. Response, toxicity and renal function pre- and post-therapy were evaluated. Eight FIGO stage IIIB and one IVB patients were treated. Pre-treatment serum creatinine ranged from 1.6 to 18.5 mg/100 ml (median 3.3, mean 6.8) and creatinine clearance varied from 4 to 57 mg/ml/min (median 17, mean 22.1). Four patients had a percutaneous nephrostomy placed and four patients had symptoms from kidney failure. All patient completed chemoradiation. Most patients had grade 3 leukopenia and neutropenia. Dermatitis, colitis and proctitis were common. All patients had improvement in creatinine clearance (pre-therapy 22.78, post-therapy 54.3 mg/ml/min) (p=0.0058) and all but one normalized serum creatinine. Eight (89%) of nine patients achieved complete response and one patient had persistence. At a median follow-up of 11 months (range 6-14), all patients are alive, one with pelvic and another with systemic disease. Ureteral obstruction causing any degree of renal insufficiency should not be a contraindication to receive chemoradiation to attempt cure. In this setting where cisplatin-based therapy is contraindicated, the use of gemcitabine may be considered.

The hamster cheek pouch as a model of oral cancer for boron neutron capture therapy studies: selective delivery of boron by boronophenylalanine.

Herein we propose and validate the hamster cheek pouch model of oral cancer for boron neutron capture therapy (BNCT) studies. This model serves to explore new applications of the technique, study the biology and radiobiology of BNCT, and assess the uptake of boron compounds and response of tumor, precancerous tissue, and clinically relevant normal tissues. These issues are central to evaluating and improving the therapeutic gain of BNCT. The success of BNCT is dependent on the absolute amount of boron in the tumor, and the tumor:blood and tumor:normal tissue boron concentration ratios. Within this context, biodistribution studies are pivotal. Tumors were induced in the hamsters with a carcinogenesis protocol that uses dimethyl-1,2-benzanthracene and mimics spontaneous tumor development in human oral mucosa. The animals were then used for biodistribution and pharmacokinetic studies of boronophenylalanine (BPA). Blood, tumor, precancerous pouch tissue surrounding tumor, normal pouch tissue, tongue, skin, cheek mucosa, palate mucosa, liver, and spleen, were sampled at 0-12 h after administration of 300 mg BPA/kg. The data reveal selective uptake of BPA by tumor tissue and, to a lesser degree, by precancerous tissue. Mean tumor boron concentration was 36.9 +/- 17.5 ppm at 3.5 h and the mean boron ratios were 2.4:1 for tumor:normal pouch tissue and 3.2:1 for tumor:blood. Higher doses of BPA (600 and 1200 mg BPA/kg) increased tumor uptake. Potentially therapeutic absolute boron concentrations, and tumor:normal tissue and tumor:blood ratios can be achieved in the hamster oral cancer model using BPA as the delivery agent.

Radio-quimioterapia concomitante en cáncer escamocelular avanzado en cabeza y cuello / Concomitant radio-chemotherapy in advanced head and neck squamocellular cancer

La radioquimioterapia concomitante aparece en los últimos años como una alternativa en el manejo de los pacientes portadores de cáncer avanzados de cabeza y cuello. En el Servicio de Otorrinolaringología del Hospital Carlos Van Buren planificamos un protocolo de estudio en pacientes portadores de cáncer escamocelular avanzados de cabeza y cuello, consistente en radioquimioterapia concomitante, 2 Gy diarios por 5 días semanales, completando 6600 a 7000 rad. asociado a cisplatino en dosis de 100 mgr/m² cada 21 días por 3 veces (los días 1,22 y 43). 30 pacientes se incluyeron en el estudio. 28 fueron analizados: 25 hombres y 3 mujeres. La edad promedio fue de 64 años. 8 casos correspondían al estadio III y 20 a estadio IV. 12 casos de localización en hipofaringe, 8 en laringe, 4 en orofaringe, 3 en cavidad oral y 1 en pirámide nasal. Se observó respuesta completa en 18 pacientes (64 por cientos), respuesta parcial en 9 pacientes (32 por ciento) y no respuesta en 1 paciente (4 por ciento). La sobrevida general fue de un 64,3 por ciento. La toxicidad renal y hematológica fueron los efectos adversos más comunes

Intratumoral and parametrial infusion of a 3-nitrotriazole (AK-2123) in the radiotherapy of the uterine cervix cancer: stage II-III--preliminary positive results.

Based on a clinical differential effect of the action of a new hypoxic cell radiosensitizer, AK-2123 (a 3-nitro-1,2,4-triazole), on locally advanced cervix cancer (Stage II-B and III-B), a Phase I/II clinical trial has been carried out on 80 consecutive patients. They were intratumorally injected with AK-2123, wt 1% and 2%, 30 min before the delivery of external radiation therapy. The short-term effects show that exophytic types of lesions respond far better than endophytic types and AK-2123 may be replacing intracavitary radium for exophytic Stage II-B cervix cancer as the standard therapy for this neoplasm in our patients. Treatment is well tolerated and no neurological toxicity has been noted.

Intra-cerebral ventricular infusion of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer in the treatment of a rat glioma.

The efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when administered by continuous infusion into the cerebral spinal fluid (CSF) of the lateral cerebral ventricle was evaluated in a 9L gliosarcoma rat brain tumor model. Stereotactic implantation of a 5 x 10(4) tumor cell suspension into the left caudate nucleus was carried out in four groups of 10 rats each. Control animals had a median survival of 16.9 days (range 16-21 days). IUDR, 8.4 mg over 7 days administered by continuous infusion into the left lateral ventricle produced a slight survival advantage (median survival 21.5 days, range 12-56). Irradiation of the entire brain, 8 Gy on days 4, 6 and 7 after tumor cell implantation also produced a slight improvement in survival (median 19.5 days, range 17-34). The combination of radiation and IUDR infusion into the CSF produced a marked survival advantage (median 30.5, range 22-54) compared to the control and single modality treatment groups. This is the first demonstration of the effectiveness of IUDR as a radiosensitizer when administered into the lateral cerebral ventricle in the treatment of an intraparenchymal brain tumor.

5-Iodo-2-deoxyuridine administered into the lateral cerebral ventricle as a radiosensitizer in the treatment of disseminated glioma.

A rat brain tumor model (Fischer 344 rats) with the clinical and pathological features of dissemination via the cerebrospinal fluid (CSF) pathways was used to demonstrate the efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when it is administered directly into the CSF. Stereotaxic implantation of 9L gliosarcoma cells (5 X 10(5) into the CSF of the lateral cerebral ventricle resulted in widespread dissemination and median survival of 18.5 and 20 days (range, 10-22) in two experiments. A continuous 7-day infusion of IUDR into the CSF starting on the day of tumor implantation did not provide any beneficial effect. Irradiation of the cranial spinal axis with 800 rad on days 4, 6, and 7 after implantation achieved an increase in survival time that was modest but statistically significant. However, the combination of IUDR infusion and radiotherapy resulted in marked improvement in survival time and a 10% cure rate (two of 20 rats). This is the first demonstration in vivo that IUDR administered into the CSF can be a potent radiosensitizer.