In vitro and in vivo studies of a newly synthesized copper-cetyl tri-methyl ammonium bromide combined with gallium oxide nanoparticles complex as an antitumor agent against hepatocellular carcinoma.

Objective: Hepatocellular carcinoma (HCC) is one of the most leading causes of death worldwide. Previous studies reported that gallium alone and cetyltrimethylammonium bromide (CTAB) have antineoplastic activities; therefore, this study aimed to evaluate the activity of copper-cetyl tri-methyl ammonium bromide with gallium oxide nanoparticles (Cu-CTAB+GaO-NPs) against HCC by using in vitro and in vivo studies. Methods: In vitro study was performed to evaluate the cytotoxic effects of Cu-CTAB+GaO-NPs and GaO-NPs on HepG-2 cell line using crystal violet dye assay. In vivo study was done on diethyl nitrosamine (DEN) induced HCC Wister rats. Rats were randomly divided into eight groups; control, Cu-CTAB, GaO-NPs, Cu-CTAB+GaONPs, DEN, DEN+Cu-CTAB, DEN+GaO-NPs and DEN+Cu-CTAB+GaO-NPs. Histopathological examination of liver and biochemical parameters such as liver function markers, oxidative stress-antioxidants markers, tumor makers, apoptosis makers were studied. Results: Results obtained from in vitro study revealed that Cu-CTAB+GaO-NPs and GaO-NPs affect the cell viability of HepG-2 cancer cell with IC50 0.2 µg/ml and 360 µg/ml, respectively. Cu-CTAB+GaO-NPs exerted an antiproliferative effect in experimental rat models of HCC, as demonstrated both histologically, since it facilitated the tissue recovery of the damaged liver, and biochemically as showed by the reduction of liver function markers (ALT & AST), oxidative stress markers (MDA) and tumor makers (AFP,TGF-ß1,α-L-Fucosidase); while antioxidants markers (SOD), apoptosis markers (caspase-3 mRNA) and araginase activity were elevated in DEN+Cu-CTAB, DEN+GaO-NPs and DEN+Cu-CTAB+GaO-NPs groups when compared to DEN group. Conclusion: The present study demonstrated that both Cu-CTAB alone and/or combined with GaO-NPs exerted cytotoxic effects against DEN-induced HCC, which would in turn, speculate a possible therapeutic role of the novel Cu-CTAB+GaO-NPs compound.

Physiological status and functional anatomy of zebra fish (Danio rerio) exposed to various levels of Ga3.

Gallium (Ga) is one of the intermetallic elements that has been used in cancer treatment for a long time. However, Ga compounds are increasingly being used to make high-speed semiconductors and photoelectric devices. The current work investigated physiological and pathological changes in zebra fish (Danio rerio) exposed to various Ga3+ levels (0.55, 1.5, and 3.85 mg/L) over a 14-day test period. Decreases in oxygen consumption were significant (p < 0.05) for groups exposed to 3.85 Ga3+ mg/L; this was associated with the fusion of zebra fish gills lamellae. Serum biochemical changes (including aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) were consistent with observations of damage to organelles within the hepatocytes at higher Ga3+ exposure levels (1.5 and 3.85 mg/L) in zebra fish. We propose <0.55 Ga3+ mg/L as a biologically safe concentration that can be used to establish water quality criteria for this teleost model.

Osteogenic response and osteoprotective effects in vivo of a nanostructured titanium surface with antibacterial properties.

In implantology, as an alternative approach to the use of antibiotics, direct surface modifications of the implant addressed to inhibit bacterial adhesion and to limit bacterial proliferation are a promising tactic. The present study evaluates in an in vivo normal model the osteogenic response and the osteointegration of an anodic spark deposition nanostructured titanium surface doped with gallium (ASD + Ga) in comparison with two other surface treatments of titanium: an anodic spark deposition treatment without gallium (ASD) and an acid etching treatment (CTR). Moreover the study assesses the osteoprotective potential and the antibacterial effect of the previously mentioned surface treatments in an experimentally-induced peri-implantitis model. The obtained data points out a more rapid primary fixation in ASD and ASD + Ga implants, compared with CTR surface. Regarding the antibacterial properties, the ASD + Ga surface shows osteoprotective action on bone peri-implant tissue in vivo as well as an antibacterial effect within the first considered time point.

Treating cancer-related hypercalcemia with gallium nitrate.

Gallium nitrate is an approved therapy for symptomatic, cancer-related hypercalcemia unresponsive to adequate hydration, the most common life-threatening metabolic disorder of cancer. Initially developed because of its antineoplastic properties, gallium nitrate demonstrated the ability to reduce serum calcium levels in early trials. Although the mechanism by which gallium nitrate corrects hypercalcemia is not fully understood, it appears to involve multiple effects (inhibition of osteoclast-mediated bone resorption, stimulation of bone formation, and alteration of the mineral composition and properties of bone); however, gallium nitrate is not cytotoxic to bone cells. In randomized trials for moderate-to-severe cancer-related hypercalcemia, gallium nitrate was well tolerated and produced a higher rate and longer duration of normocalcemia relative to calcitonin and the bisphosphonates etidronate and pamidronate. Gallium nitrate induced normocalcemia in 72% to 82% of patients; in contrast to the comparator agents, it was effective regardless of epidermoid tumor status. Epidermoid tumors are associated with high levels of parathyroid hormone-related protein (PTHrP), the principal mediator of cancer-related hypercalcemia in solid tumors. High levels of PTHrP appear to adversely impact the calcium-lowering potential of bisphosphonates. The recommended schedule of gallium nitrate for the treatment of cancer-related hypercalcemia is 200 mg/m2 per day as a 5-day continuous intravenous infusion, administered with adequate hydration and close monitoring of renal function. Gallium nitrate is an effective treatment option for moderate-to-severe cancer-related hypercalcemia, a setting in which morbidity and mortality are high.

Apoptotic mechanisms of gallium nitrate: basic and clinical investigations.

Gallium nitrate inhibits the growth of various lymphoma cell lines in vitro and exhibits antitumor activity in patients with lymphoma. The mechanism(s) of cytotoxicity is (are) only partly understood but appears to involve a two-step process: (1) targeting of gallium to cells, and (2) acting on multiple, specific intracellular processes. Gallium shares certain chemical properties with iron; therefore, it binds avidly to the iron transport protein transferrin. Transferrin-gallium complexes preferentially target cells that express transferrin receptors on their surface. Expression of transferrin receptors is particularly high on lymphoma cells. Cellular uptake of the gallium-transferrin complex leads to inhibition of cellular proliferation primarily via disruption of iron transport and homeostasis and blockade of ribonucleotide reductase. Recent studies have shown that cellular uptake of gallium leads to activation of caspases and induction of apoptosis. In phase II trials in patients with relapsed or refractory lymphoma, the antitumor activity of gallium nitrate is similar to, or better than, that of other commonly used chemotherapeutic agents. Gallium nitrate is not myelosuppressive and may be used in patients with neutropenia or thrombocytopenia. A multicenter trial to evaluate the use of gallium nitrate in patients with relapsed non-Hodgkin's lymphoma is currently ongoing.

Dental post-operative sensitivity associated with a gallium-based restorative material.

INTRODUCTION: This study forms part of a 2-year longitudinal clinical trial to compare the performance of a gallium-based restorative material (Galloy) with a high copper, mercury based (Dispersalloy) control material. METHOD: Following Ethical Committee approval, 25 galloy restorations and 25 Dispersalloy controls were placed in 14 adult patients, by a single operator. The cavities were of moderate size, indicating the use of amalgam as the restorative material. All restorations were polished within 1 week of placement, photographed and a silicone impression of the tooth and restoration recorded. In addition, a visual analogue scale (VAS), indicating the extent of any post-operative sensitivity, was completed by each patient for each restoration, immediately prior to polishing. A score of 0 indicated no sensitivity, while a score of 10 indicated the greatest possible sensitivity. At 6-month recall, the VAS scores, silicone impressions and photographs were repeated. RESULTS: The mean sensitivity scores for the galloy and Dispersalloy restorations at 1 week were 5.1 (+/- 3.4) and 1.0 (+/- 1.5), respectively and at 6 months, 1.8 (+/- 3.0) and 0.2 (+/- 0.1) respectively. The differences between these means at 1 week and at 6 months were significant (P < 0.01). CONCLUSION: Galloy restorations were associated with a much greater severity of post-operative sensitivity than Dispersalloy restorations.

Risk of respiratory exposure of dental personnel to amalgam alternatives.

Although the use of alternatives to dental amalgam is increasing, the possible hazard associated with their occupational exposure has received inadequate attention. The purpose of this study is to use available toxicological and environmental information in a qualitative risk assessment to address potential health hazards associated with exposure to these materials by dental personnel. The members of dental profession should be aware of risk due to long-term exposure to dental materials.

A phase II trial of gallium nitrate in patients with androgen-metastatic prostate cancer.

INTRODUCTION: Due to in vitro data suggesting antitumor activity with gallium nitrate, we sought to evaluate the safety and activity in patients with androgen-independent prostate cancer. METHOD: Patients were eligible for this study if they had an ECOG performance status of < or = 2, stage D2 metastatic prostate cancer that was progressing following combined androgen ablation (medical or surgical castration plus antiandrogen) and had failed antiandrogen withdrawal. Therapy consisted of gallium nitrate (200 mg/m(2)/day) as a continuous infusion for 7 days, administered every 21 days, with hydration (100 ml/m(2)/h). Individuals that had previously received suramin were treated at a dose of 150 mg/m(2)/day of gallium nitrate. RESULTS: Eight patients were enrolled: 4 patients at the 200 mg/m(2)/day dose level and 4 patients at the lower dosage (150 mg/m(2)/day). One of 8 patients had a >75% decline in prostate-specific antigen (PSA), 3 patients had stable PSA values for 17, 18 and 22 weeks, and 4 patients had progression by PSA (>50% increase over baseline). Anemia requiring transfusion occurred in 5 of 8 patients (63%). Two patients (25%) developed grade 4 toxicity: 1 patient developed complete blindness with partial reversal over 12 months, and another patient had pulmonary infiltrates, hypoxemia, and fever. Serious adverse events were not correlated to prior suramin exposure, or gallium plasma concentrations (total or free), but appeared to be related to cumulative cycles of gallium nitrate. Remaining adverse events were grade 1 or 2. No patients developed renal or neurological toxicity. CONCLUSION: This trial was prematurely terminated because repeated administration of gallium nitrate was poorly tolerated in an elderly population with androgen-independent prostate cancer. Gallium had modest clinical activity in this disease.

Therapeutic uses of gallium nitrate: past, present, and future.

Injectable gallium (Ga) nitrate, approved in the United States for the treatment of hypercalcemia of malignancy, has been known for more than 2 decades to have immunosuppressive properties. At therapeutic doses, it has few adverse effects, although high-dose infusions may result in severe nephrotoxicity, particularly in patients who are not adequately hydrated, and severe anemia. In animal models, Ga has been shown to have efficacy in the treatment of adjuvant arthritis, type 1 diabetes, experimental autoimmune encephalomyelitis, experimental pulmonary inflammation, cardiac allograft rejection, experimental autoimmune uveitis, endotoxic shock, and systemic lupus erythematosus. Clinical trials have demonstrated efficacy in Paget's disease of bone and activity against some malignancies, including epithelial ovarian carcinoma, non-squamous cell carcinoma of the cervix, bladder cancer, and non-Hodgkin's lymphoma. Other clinical trials underway include studies of sarcoidosis and rheumatoid arthritis. Future studies should be conducted not only in other autoimmune diseases, such as multiple sclerosis, but also in graft-versus-host disease, leprosy, and acquired immunodeficiency syndrome (AIDS).

Gallium nitrate optic neuropathy.

PURPOSE: To report a patient with visual loss after systemic administration of gallium nitrate. METHOD: Case report. RESULTS: After receiving intravenous gallium nitrate, a 77-year-old man developed bilateral visual loss and optic neuropathy with central scotomas on visual field testing and diminished P2-wave amplitude on visual evoked potential examination. The condition worsened after oral corticosteroid therapy. Partial recovery of optic nerve function in both eyes was present after 12 months of oral ferrous sulfate administration. CONCLUSIONS: Partially reversible bilateral optic neuropathy may occur after administration of gallium nitrate in the absence of other chemotherapeutic agents. Ophthalmic examinations are indicated in patients who receive gallium nitrate.

Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.

PURPOSE: A phase II randomized trial of gallium nitrate/fluorouracil (5-FU) versus dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was performed in poor-risk patients with advanced urothelial tract tumors. The efficacy and toxicity of these regimens were compared. Assessment of dose-intense M-VAC as salvage treatment in patients who failed to respond to the gallium nitrate/5-FU regimen was also performed. PATIENTS AND METHODS: Thirty-four patients who had not received prior systemic chemotherapy were randomized to either arm of the study. All patients had one or more clinical features predicting a low likelihood of durable complete response to standard chemotherapy, ie, weight loss, visceral metastases, and low performance status. Gallium nitrate and 5-FU were each administered by continuous 5-day infusions every 28 days. M-VAC was recycled every 21 days, with prophylactic recombinant human granulocyte colony-stimulating factor (rh-G-CSF). RESULTS: Two of 17 patients (12%; 95% confidence interval [CI], 1.4% to 36.4%) had a major response to gallium nitrate/5-FU. Sixteen of 17 patients treated with M-VAC (94%; 95% CI, 71.3% to 99.8%) demonstrated a major response. Five of 12 patients who failed to respond to the gallium nitrate/5-FU combination responded to M-VAC as second-line therapy (42%; 95% CI, 15.2% to 72.3%). Median survival for the gallium nitrate and 5-FU arm was 19 versus 17 months for the M-VAC arm, with a median follow-up duration of 35 months (range, 2 to 51) for all patients. Dose-intense M-VAC was associated with a greater incidence of neutropenia and thrombocytopenia. CONCLUSION: Dose-intense M-VAC is superior to gallium nitrate/5-FU in poor-risk patients (P < .0001). Despite the overall high response rate, the median survival for patients with M-VAC remained unsatisfactory. Similar survival distributions were observed for patients who received investigational therapy followed by cisplatin-based therapy and patients treated with initial cisplatin-based therapy.

Evaluation of continuous-infusion gallium nitrate and hydroxyurea in combination for the treatment of refractory non-Hodgkin's lymphoma.

Based on preclinical studies demonstrating synergy between gallium and hydroxyurea, we evaluated the efficacy and toxicity of continuous intravenous gallium nitrate in combination with oral hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients, median age 64 years (range 53-89), with stage III or IV low- or intermediate-grade lymphoma were treated with gallium nitrate and hydroxyurea in combination for 7 days at four different dose levels: (a) gallium nitrate, 200 mg/m2/day; hydroxyurea, 500 mg/day; (b) gallium nitrate, 250 mg/m2/day; hydroxyurea, 1,000 mg/day; (c) gallium nitrate, 300 mg/m2/day; hydroxyurea, 1,000 mg/day; and (d) gallium nitrate, 350 mg/m2/day, hydroxyurea, 1,000 mg/day. All patients had progressive disease and had been heavily pretreated. Six of 14 patients had objective tumor regression following treatment (one complete response, one near-complete response, and four partial responses) with a median duration of response of 7 weeks (range 3-38 weeks). An additional four patients had minor responses. Responses occurred at all dose levels and in both low- and intermediate-grade histologic subtypes. The predominant toxicities encountered were anemia and reversible nephrotoxicity. Combination gallium nitrate and hydroxyurea has significant activity in lymphoma and is well tolerated even by elderly patients. Because of the lack of cross-resistance to other drugs and the potential synergistic antineoplastic activity, gallium nitrate and hydroxyurea should be further evaluated in combination with other chemotherapeutic agents.

[Gallium: an alternative for amalgam?]. / Gallium: een alternatief voor amalgaam?

Some of the physical properties of gallium-based dental alloys for restorative goals equal those of dental silver amalgam, but the results of the relatively few and short-term studies of their clinical behaviour differ. Corrosion, discoloration, rough surface, expansion and fractures of the margins and possibly the teeth, may pose serious problems and are assessed to make the clinical use premature. Handling characteristics are less favourable than for silver amalgam. Gallium alloys release a substantial amount of gallium. Results of toxicity studies with cell cultures differ. Compared to some brands of silver amalgams the alloys seem to be somewhat more cytotoxic during a longer period of time. However, the gallium released by the restorations would be insufficient to harm the patients. Implants of (early) alloys evoked more serious reactions than silver amalgam. Sensitization is not reported, but few restorations have been made and allergic studies are scarce.

2-year clinical evaluation of a gallium restorative alloy.

PURPOSE: To assess the clinical performance of 2-year old gallium alloy restorations. Parameters evaluated include: (1) fracture at the margins, (2) tarnish, (3) surface roughness, (4) tooth fracture, (5) fracture through the body of the restoration, and (6) any medical or dental conditions arising during the study. MATERIALS AND METHODS: Nine patients received 30 Class I restorations of Galloy gallium alloy. These were placed as conservatively as possible under a rubber dam. Fifteen of the preparations were lined with a Bis-GMA resin to seal the restoration from moisture. The other 15 preparations were sealed with Amalgambond. After placement of the gallium alloy, the exposed surfaces of all restorations were sealed with the Bis-GMA resin, and the occlusion was checked. The restorations were examined at 2 weeks, 3 months, 6 months, 1 year and 2 years. RESULTS: At the 2-year recall, all restorations were intact with the exception of one tooth fracture (cause unknown). Forty-five percent of the restorations exhibited tarnish and 60% had a rough surface. The fracture at the margins of these restorations was minimal, and no significant difference could be found between those using Amalgambond and those sealed with the resin system. No medical problems were reported by the patients, and postoperative sensitivity was minimal.

Clinical evaluation of gallium alloy as a posterior restorative material.

This study evaluated 30 gallium alloy (Gallium alloy GF) and 31 amalgam (Dispersalloy) restorations over a period of 8 months in both Class I and Class II cavity preparations in 28 human subjects. At baseline, all gallium alloy and amalgam restorations were considered acceptable (Alfa) in terms of caries, anatomic form, marginal adaptation, surface texture, and bulk fracture. Postoperative sensitivity was reported in 67% of the gallium alloy restorations and in 29% of the amalgam restorations. At 8 months, 61% of the gallium alloy restorations were rated Beta for marginal adaptation, and all restorations exhibited tarnish and corrosion. With a few exceptions, the amalgam restorations were rated Alfa for those criteria. Three gallium alloy restorations had to be replaced during the evaluation period because of severe postoperative sensitivity and 39% of gallium restorations still presented some sensitivity at 8 months. Additional problems exhibited by gallium restorations were tooth fractures, tooth cracks, and marginal whitening.

A phase II trial of gallium nitrate (NSC #15200) in nonsquamous cell carcinoma of the cervix. A Gynecologic Oncology Group study.

A Phase II trial of gallium nitrate for patients with recurrent or metastatic nonsquamous cell carcinoma of the cervix was conducted by the Gynecologic Oncology Group (GOG) from March 1988 to January 1992. Twenty-six evaluable patients were treated with 750 mg/m2 of gallium nitrate every 3 weeks. Age range was 30-74 years with a median of 48 years. GOG performance status was 0-1 for all but four patients. Two patients had a complete response (7.7%), 1 patient had a partial response (3.8%), 13 patients had stable disease (50.0%), and 10 (38.5%) had increasing disease. The 95% confidence interval for response is 2.4-30.2%. The major toxicities were nausea, vomiting, and anemia. Gallium nitrate has modest activity in patients with nonsquamous cell carcinoma of the cervix.

A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone.

Gallium nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day gallium nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross-links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of gallium nitrate is safe and effective for treating patients with advanced Paget's disease of bone.