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PubMed2003

Gallium nitrate in the treatment of lymphoma.

Gallium nitrate is effective and well tolerated for the treatment of cancer-related hypercalcemia. At somewhat higher doses, gallium nitrate also has cytotoxic activity against a variety of cancers. The probable mechanism is inhibition of both ribonucleotide reductase and a protein tyrosine phosphatase. Radioactive gallium ((67)Ga) is concentrated at sites of malignant lymphoma, Hodgkin's disease, and other tumors. Gallium nitrate has substantial single-agent activity in the treatment of patients with advanced lymphoma and has also shown activity when used in combination with other agents. Significant response rates have been observed in patients with diffuse large cell lymphoma, small lymphocytic lymphoma, and follicular lymphoma. Because of its unique mechanism of action, gallium nitrate could be non-cross-resistant with many of the cytotoxic agents used as standard chemotherapy for non-Hodgkin's lymphoma. Nephrotoxicity, the most frequent adverse event associated with gallium nitrate, can generally be minimized by ensuring adequate oral hydration and avoiding concomitant use of other nephrotoxic drugs. Gallium nitrate causes little myelosuppression and is therefore well tolerated by patients with advanced disease who have received extensive prior therapy. Given its unique mechanism of action, the high level of single-agent activity in published clinical trials, the absence of significant myelosuppression, and the potential lack of cross-resistance, further clinical study of gallium nitrate both alone and in combination with other active agents is warranted.

Antineoplastic Agents↗
PubMed1997

In vitro effect of gallium nitrate when combined with ketoconazole in the prostate cancer cell line PC-3.

Secondary hormonal manipulations are common following the failure of combined androgen blockade in patients with metastatic prostate cancer. Ketoconazole has been shown to have activity in this disease by inhibiting cytochrome P450 steroid hormone biosynthesis, thus inducing androgen deprivation. Gallium nitrate has been reported to target tumor tissue in vitro and some preliminary data suggests activity in patients with prostate cancer. Thus, we conducted a Phase II study of gallium nitrate in patients with androgen-independent prostate cancer. Two patients with progressive prostate cancer were removed from this study and subsequently placed on ketoconazole, as a palliative agent. Surprisingly, both of these patients had a greater than 50% decline in their prostate specific antigen (PSA) with this secondary endocrine maneuver. Based on this clinical observation, we conducted the following in vitro study to determine if there was a substantial additive effect of gallium nitrate followed by ketoconazole. Gallium nitrate or ketoconazole was added to the androgen-independent prostatic epithelial cell line, PC-3. One hundred and twenty hours (120 h) following the addition of one of the agents, the media was aspirated and the second agent was added to the wells. One plate was assayed every 24 h for cell viability using a non-isotopic cell proliferation assay kit. Cells treated with gallium nitrate followed by ketoconazole were 70-100% of control at the end of the gallium nitrate treatment; ketoconazole was then added and viability either remained constant or dropped steadily. Gallium nitrate by itself had a weak inhibitory effect on cell viability that only became apparent at the highest concentration evaluated. Ketoconazole, on the other hand, showed a substantial growth inhibition that was concentration-dependent. Cells treated with this agent alone showed a pronounced steady decrease in viability. Exposure to ketoconazole for 120 h followed by incubation in culture medium alone for 120 h caused a decrease in cell viability to 26.0% of control. Our in vitro results suggest that the combination of gallium nitrate and ketoconazole has no additive activity in the PC-3 cell line. Furthermore, this study confirms that ketoconazole added to prostate cancer cells has antiproliferative activity. The in vitro activity of ketoconazole has traditionally been thought to result from its inhibition of cytochrome P450-dependent enzymes responsible for steroidogenesis; however, an alternative hypothesis is necessary to explain the cytotoxic effect in the absence of adrenal and testicular androgen production as found in an in vitro system.

Antifungal Agents↗
PubMed1998

Value of gallium-67 scintigraphy in monitoring the renal activity in lupus nephritis.

In this study, we evaluated the relationship between the gallium uptake in the kidneys and the results of renal biopsy. The renal uptake of gallium in 32 patients with lupus nephritis were evaluated according to the classification of the World Health Organization, the activity index (AI), and the chronicity index (CI). AI was significantly higher in patients with a positive gallium scan when compared with patients with a negative gallium scan (p = 0.0007). However, change in gallium uptake was not related to the CI or WHO classification (p = 0.68 and p = 0.79 respectively). Of the 16 patients with AI > or = 9, 13 (81.25%) had a positive gallium scan, while only 3 (18.7%) of the patients with AI < 9 had a positive scan. In addition, all patients (100%) with AI > or = 11 showed a positive gallium scan. We conclude that renal imaging with gallium has a good correlation with AI, and may be a useful alternative to renal biopsy in patients with lupus nephritis.

Adolescent↗
PubMed1975

Distribution of anticancer agents in spontaneous animal tumors. II. Distribution of gallium in canine lymphosarcoma.

The physiologic disposition of pharmacologic doses of gallium was studied in control dogs and dogs with spontaneous lymphosarcoma. Gallium 67 (67Ga) was administered iv with carrier gallium added at a dose of 8 mg/kg. About 50% of the injected dose was excreted in the urine by 48 hours (mostly in the first 12 hr), whereas negligible amounts were excreted in bile. The distribution of 67Ga in normal tissues was similar in control and tumor-bearing dogs. The tissue-to-plasma concentrations of gallium were considerably greater than 1 in the kidney cortex, bone marrow, bone, small intestine, and liver 6-72 hours after administration of the drug. At comparable time periods, tissue-to-plasma ratios of gallium were less than 1 in skeletal muscle and brain. In dogs with lymphosarcoma there was neither selective uptake nor selective retention of gallium in comparison to most normal tissues. In fact, several normal tissues, particularly kidney cortex and bone marrow, concentrated gallium greatly in excess of tumors. Qualitatively similar findings were obtained in a dog with malignant melanoma. These findings were contrary to what one would predict from reports showing that carrier-free 67Ga is selectively concentrated in various human and animal tumors. This indicates the need for more extensive studies of the physiologic disposition of pharmacologic (antitumor) doses of gallium in humans and appropriate animal models.

Animals↗
PubMed2003

Hilar and pancreatic gallium-67 accumulation is characteristic feature of autoimmune pancreatitis.

INTRODUCTION AND AIMS: Autoimmune pancreatitis is characterized by severe lymphocytic inflammation, suggesting that gallium-67 scintigraphy provides a useful tool for detecting characteristic lesions of this disease, because gallium-67 concentrates in lymphoid cells. We tried to determine whether gallium-67 accumulates in the characteristic lesions. METHODOLOGY: We performed gallium-67 scintigraphy in 24 patients with autoimmune pancreatitis before and after 4 weeks of corticosteroid therapy and determined the factors associated with positive images. RESULTS: Sixteen patients (67%) had marked gallium-67 accumulation in the pancreas before corticosteroid therapy and negative images after 4 weeks of therapy, and they had significantly higher serum IgG4 values than did those without gallium-67 accumulation (median, 758 mg/dL versus 329 mg/dL; p = 0.011). Marked hilar gallium-67 accumulation was found in 16 patients (67%) and was also associated with significantly higher serum IgG4 values than did those without it (median, 758 versus 239 mg/dL; p = 0.0044). Among 16 patients with positive hilar images, 12 had positive pancreatic uptake and 5 had both pancreatic and salivary gland uptakes. CONCLUSIONS: Hilar and pancreatic accumulation of gallium-67 is a characteristic feature of autoimmune pancreatitis during the active stage of the disease, when IgG4 serum levels are high.

Adrenal Cortex Hormones↗
PubMed1999

Intracranial mass lesions: sequential thallium and gallium scintigraphy in patients with AIDS.

PURPOSE: To determine the efficacy of sequential thallium and gallium scintigraphy to differentiate intracranial neoplasms (lymphoma and glioma) from other nonmalignant intracranial mass lesions among patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: The authors reviewed the cases of 40 patients with human immunodeficiency virus (HIV) who underwent thallium and gallium scanning to evaluate intracranial mass lesions from October 1991 through November 1997. There was a definitive final diagnosis of the nature of the mass lesions in 21 of these cases. In these 21 cases, the scintigraphic patterns were reviewed and were compared with the final diagnosis. RESULTS: On the basis of results at thallium and gallium scanning, the patients were divided into three groups. Group A included 13 patients (11 with brain tumors [lymphomas and gliomas] and two with progressive multifocal leukoencephalopathy [PML]) with thallium-positive, gallium-positive scans. Group B included five patients with intracranial infections (tuberculosis, Cryptococcus, bacteria) with thallium-negative, gallium-positive scans. Group C included three patients (one with PML and two with infarcts) with thallium-negative, gallium-negative scans. All patients with lymphomas were in group A. The sensitivity and specificity of the thallium-positive, gallium-positive pattern for intracranial malignancy were 100% and 80%, respectively. CONCLUSION: Sequential thallium and gallium scanning helped differentiate tumors from nonmalignant intracranial mass lesions and may help differentiate infections from PML or infarcts.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium.

We have previously shown that human leukemic cells proliferate normally in serum-free media containing various transferrin forms, but the addition of transferrin-gallium leads to inhibition of cellular proliferation. Because gallium has therapeutic potential, the effects of transferrin-gallium on leukemic cell proliferation, transferrin receptor expression, and cellular iron utilization were studied. The cytotoxicity of gallium is considerably enhanced by its binding to transferrin and cytotoxicity can be reversed by transferrin-iron but not by other transferrin forms. Exposure to transferrin-gallium leads to a marked increase in cell surface transferrin binding sites, but despite this, cellular 59Fe incorporation is inappropriately low. Although shunting of transferrin-gallium to another cellular compartment has not been ruled out, other studies suggest that transferrin-gallium impairs intracellular release of 59Fe from transferrin by interfering with processes responsible for intracellular acidification. These studies, taken together, demonstrate that inhibition of cellular iron incorporation by transferrin-gallium is a prerequisite for inhibition of cellular proliferation.

Cell Division↗
PubMed1995

Ultrastructural and histomorphometric evaluations of gallium nitrate on bone in nude mice bearing a canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy.

Gallium is a group IIIa transition metal that lowers serum calcium by an unknown mechanism and has been utilized in the treatment of cancer-associated hypercalcemia. The purpose of this study was to histomorphometrically investigate the ultrastructural effects of gallium nitrate on osteoclasts and osteoblasts in trabecular bone of normal nude mice and nude mice with humoral hypercalcemia of malignancy. Two groups of normal nude mice (n = 7 and n = 8, respectively) and two groups of hypercalcemic nude mice (n = 9) bearing a serially transplantable canine adenocarcinoma (CAC-8) were treated with vehicle or gallium nitrate. Osteoclasts were hypertrophied in vehicle-treated tumor-bearing nude mice as compared with vehicle-treated nontumor-bearing nude mice. Osteoclasts from tumor-bearing nude mice treated with gallium nitrate were significantly decreased in size and had fewer intracytoplasmic vesicles as compared with osteoclasts from vehicle-treated tumor-bearing nude mice. Degenerate osteoclasts, characterized by pyknotic nuclei and increased cytoplasmic vacuolation, were observed in both groups of gallium-treated nude mice. Osteoblasts from vehicle-treated tumor-bearing nude mice were hypertrophied and had extensive lamellar arrays of rough endoplasmic reticulum as compared with osteoblasts from vehicle-treated nontumor-bearing nude mice. Osteoblasts in gallium-treated nude mice (tumor-bearing and nontumor-bearing) were small and flattened with poorly developed cytoplasmic organelles. This investigation demonstrated that osteoclasts and osteoblasts in nude mice treated with gallium nitrate had ultrastructural evidence of decreased metabolic and functional activity. The results suggest that gallium nitrate lowers serum calcium by inhibiting osteoclastic bone resorption.

Adenocarcinoma↗
PubMed1992

Gallium nitrate.

OBJECTIVE: To evaluate the therapeutic role of gallium nitrate in the treatment of hypercalcemia associated with malignancy and related disease states. DATA SOURCES: A literature search of English-language studies involving gallium nitrate for the period 1966-1991 using MEDLINE and the bibliographies of relevant articles. STUDY SELECTION: Because of the limited number of studies, all clinical trials were reviewed, with particular emphasis on Phase III comparative trials. Related investigative studies on the pharmacology, pharmacokinetics, and toxicity of gallium nitrate were also reviewed. DATA EXTRACTION: Two appraisers independently abstracted data from available clinical trials and evaluated trial quality. RESULTS OF DATA SYNTHESIS: Two Phase III comparative trials evaluating gallium nitrate in the treatment of hypercalcemia of malignancy have been completed. Gallium nitrate was shown to be superior to both calcitonin and etidronate disodium, based on the comparative percentage of patients achieving normocalcemia and the subsequent duration of normocalcemia. Both trials employed similar methodology. Positive therapeutic effects of gallium nitrate have also been demonstrated in small, noncomparative trials for hypercalcemia associated with parathyroid carcinoma, Paget's disease of bone, and osteolytic bone metastases. CONCLUSIONS: Gallium nitrate is effective in the treatment of hypercalcemia associated with malignancy and is appropriate for formulary addition. In certain clinical situations, it may be clearly advantageous over such agents as calcitonin, plicamycin, and etidronate. Further investigation is needed to define the limitations of nephrotoxicity and the therapeutic potential for other indications. Further comparative clinical trials of gallium nitrate versus bisphosphonates and plicamycin could also help define its relative clinical benefit.

Gallium↗
PubMed1991

A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia.

Hypercalcemia is a major source of morbidity and mortality in patients with cancer. Gallium nitrate and the bisphosphonate, etidronate, are new agents that have recently become available for treatment of this disorder. To directly compare therapeutic effectiveness, we conducted a randomized, double-blind, multicenter study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. Gallium nitrate was administered by continuous intravenous (IV) infusion at a dose of 200 mg/m2/d. Etidronate was administered as a 4-hour IV infusion at a dose of 7.5 mg/kg. Both drugs were given daily for 5 consecutive days. Eligible patients had persistent moderate-to-severe hypercalcemia (total serum calcium [corrected for serum albumin] greater than or equal to 12.0 mg/dL) after 2 days of hospitalization and IV hydration. Seventy-one patients were randomized and treated. Twenty-eight of 34 patients (82%) who received gallium nitrate achieved normocalcemia compared with 16 of 37 patients (43%) who received etidronate (P less than .001). Patients who received etidronate required significantly greater amounts of IV fluids (P = .04) and more hypocalcemic drug treatment (P less than .05) during the poststudy period than patients who received gallium nitrate. Kaplan-Meier analysis showed a significantly longer median duration of normocalcemia for patients treated with gallium nitrate (8 days v 0 days, P = .0005). A significantly higher proportion of patients treated with gallium nitrate developed asymptomatic hypophosphatemia compared with patients treated with etidronate (97% v 43%, P less than .001). We conclude that gallium nitrate is highly effective and superior to etidronate for acute control of moderate-to-severe cancer-related hypercalcemia.

Adult↗
PubMed1995

Diagnostic and prognostic value of myocardial scintigraphy with thallium-201 and gallium-67 in cardiac sarcoidosis.

STUDY OBJECTIVE: To examine the diagnostic and prognostic value of myocardial scintigraphy using thallium-201 and gallium-67 in cardiac sarcoidosis. PATIENTS: Twenty-five patients with sarcoidosis. METHODS: All patients underwent myocardial thallium-201 scintigraphy. Six patients with myocardial thallium-201 defects were classified into group A and another 19 without defects were classified into group B. Between group A and B, we compared the results of other noninvasive examinations, including standard 12-lead ECG, 24 h ambulatory ECG, chest radiography, measurements of serum angiotensin-converting enzyme (ACE) and lysozyme levels, and gallium-67 scintigraphy. RESULTS: Proportions of subjects who had varying degrees of heart block, severe ventricular arrhythmias (more than or equal to third grade of Lown's classification), and high levels of serum ACE and lysozyme levels were not different between these two groups (p > 0.05). Although an enlarged cardiothoracic ratio was more frequent in group A (p < 0.05), bilateral hilar lymphadenopathy was more frequent in group B (p < 0.01). Four patients of group A and 15 of group B underwent gallium-67 scintigraphy. Although no subjects of group B had myocardial uptake of gallium-67, two of four group A patients showed cardiac uptake. These four group A patients were treated with corticosteroids. The therapy provided clinical and scintigraphic improvement in two patients with myocardial gallium-67 uptake, although it did no improvement in the other two patients without gallium-67 uptake. CONCLUSIONS: When cardiac sarcoidosis was diagnosed according to myocardial thallium-201 defects, other noninvasive examinations were not useful to detect this disease. However, gallium-67 uptake may predict the efficacy of corticosteroids. Thus, the combination of thallium-201 and gallium-67 scintigraphy may be useful not only in diagnosis of cardiac sarcoidosis but also in prediction of effects of corticosteroids.

Adrenal Cortex Hormones↗
PubMed1988

Gallium nitrate for acute treatment of cancer-related hypercalcemia. A randomized, double-blind comparison to calcitonin.

STUDY OBJECTIVE: To determine whether gallium nitrate therapy is superior to maximally approved doses of calcitonin for acute control of cancer-related hypercalcemia. DESIGN: Randomized, double-blind comparison of active treatments. SETTING: Comprehensive cancer center. PATIENTS: One hundred ninety-eight consecutive hypercalcemic events in 164 patients screened for entry. ELIGIBILITY CRITERIA: hospitalization and intravenous hydration for at least 2 days; persistent elevated serum calcium levels of 2.99 mmol/L or greater (adjusted for serum albumin); serum creatinine levels of 221 mumol/L or less; no cytotoxic chemotherapy, radiation, or mithramycin within the preceding 7 days or during study; no concurrent use of aminoglycoside antibiotics; life expectancy greater than 4 weeks; lymphoma and parathyroid carcinoma excluded. Patients were stratified by histologic type of tumor (epidermoid or nonepidermoid). Fifty patients were randomized and treated. INTERVENTIONS: Gallium nitrate 200 mg/m2 body surface area for 5 days by continuous intravenous infusion, or salmon calcitonin 8 IU/kg body weight every 6 hours for 5 days by intramuscular injection. Patients randomized to receive gallium nitrate received sham injections of saline to simulate calcitonin; patients randomized to receive calcitonin received 1000 mL 5%-dextrose solution to simulate gallium nitrate. MEASUREMENTS AND MAIN RESULTS: All patients were evaluable. Eighteen of twenty-four patients who received gallium nitrate achieved normocalcemia compared with 8 of 26 patients who received calcitonin for an observed difference of 44% (95% confidence interval, 19% to 69%; P = 0.002). Median duration of normocalcemia before other cytotoxic or hypocalcemic therapy was 6 days for patients treated with gallium nitrate compared with 1 day for patients treated with calcitonin (P less than 0.001). Median duration of normocalcemia regardless of intercurrent treatment and without adjustment for serum albumin was 11+ days for patients treated with gallium nitrate and 2 days for patients treated with calcitonin (P less than 0.01). Mean daily fluid intake and mean daily dose of furosemide were similar in both treatment groups. No additional benefit was seen in 9 patients randomized to receive calcitonin who incidentally received corticosteroids. CONCLUSIONS: Gallium nitrate therapy is highly effective and superior to maximally approved doses of calcitonin for acute control of cancer-related hypercalcemia.

Adult↗
PubMedDate not supplied

C-reactive protein and gallium scintigraphy in patients after abdominal surgery.

BACKGROUND/AIMS: Early detection of post-surgical infection is important to decrease mortality in patients after operation. Both C-reactive protein test and gallium-67 scan (gallium scan) are sensitive examinations in the detection of infection. In this study, we compared the diagnostic accuracy of the two modalities in the detection of infection after abdominal surgery. METHODOLOGY: Forty-six patients undergoing abdominal surgery were enrolled in this study. All patients received blood examination for C-reactive protein test and were referred to our department for gallium scan because of unknown fever after surgery. RESULTS: Of the 46 patients with abdominal surgery, 22 (47.8%) were diagnosed to have infection including 6 intra-abdominal abscesses, 8 wound infection and 8 with both intra-abdominal abscesses and wound infection. To achieve better diagnostic results, C-reactive protein value of 2.8 mg/dL was chosen as cut-off value. The diagnostic sensitivities for both gallium scan and C-reactive protein test were 100%. The diagnostic specificity of gallium scan was superior to C-reactive protein test (83.3% vs. 54.2%). The overall diagnostic accuracy of gallium scan and C-reactive protein test were 92.6% and 76%, respectively. CONCLUSIONS: Both C-reactive protein test and gallium scan have good sensitivity in the detection of infection after abdominal surgery. Gallium scan has better diagnostic specificity than the C-reactive protein test.

Abdominal Abscess↗
PubMedDate not supplied

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.

Drug Administration Schedule↗
PubMed1990

Differential growth-inhibitory effects of gallium on B-lymphocyte lines in high versus low iron concentrations.

The growth inhibitory effects of gallium on a murine and human B-cell line were studied using two different serum-free culture systems: (a) ferric citrate medium containing 500 microM iron and (b) transferrin medium containing 5 micrograms/ml of iron-saturated transferrin (0.125 microM iron). For the human cell line in ferric citrate medium, 50% growth inhibition achieved in the presence of transferrin-gallium represented a gallium concentration 80-fold lower than the concentration required when gallium nitrate was added. In the transferrin system, significantly higher transferrin-gallium concentrations were required to achieve the same inhibitory effects. Monoclonal antibody to the transferrin receptor significantly decreased the growth inhibiting effect of transferrin-gallium in the mouse ferric citrate system. Thus, under very different culture conditions, gallium and iron appear to compete via the transferrin-transferrin receptor pathway for cellular uptake. The growth inhibitory effects of gallium are markedly potentiated when the metal is taken up by functional transferrin receptors even in cells continuously cultured in transferrin-free medium.

Animals↗
PubMed1988

Effect of gallium on DNA synthesis by human T-cell lymphoblasts.

We have studied the antiproliferative effects of gallium nitrate in cultured CCRF-CEM lymphoblasts. The 50% inhibitory dose for these cells was 120 microM, and after 24 h at a cytostatic concentration (480 microM) S-phase arrest was observed by DNA flow cytometry. Deoxyribonucleoside triphosphate pools were all reduced (dATP, dGTP, and dCTP by 50%, dTTP by 25%), suggesting inhibition of ribonucleotide reductase. Administration of tracer amounts (0.5 microM) of either [3H]uridine or [3H]deoxyuridine confirmed that DNA synthesis had been inhibited to 20% of control rates by gallium. Further, the flow of the ribonucleoside into the dTTP pool and DNA was selectively reduced compared to that of the deoxyribonucleoside. Gallium decreased the specific activity of dTTP labeled from uridine by 50%, whereas the specific activity of dTTP labeled from deoxyuridine was increased 2.5-fold. Thus counts in DNA derived from [3H]uridine were decreased by more than 80%, while counts in DNA derived from [3H]deoxyuridine were virtually unaltered. Uridine incorporation into RNA was not affected. Gallium did not significantly alter the capacity of permeabilized naive cells to incorporate [3H]dTTP into DNA, while 24-h gallium pretreatment (which increased the percentage of S-phase cells) produced a modest increase in [3H]dTTP incorporation, indicating that any effect of gallium on DNA polymerase alpha is minor. Gallium treatment did not induce or inhibit the repair of DNA single strand breaks. These data demonstrate that gallium inhibits replicative DNA synthesis, with the major specific enzyme target probably being ribonucleotide reductase.

Antineoplastic Agents↗
PubMed1994

Synergistic inhibition of T-lymphoblastic leukemic CCRF-CEM cell growth by gallium and recombinant human alpha-interferon through action on cellular iron uptake.

Gallium, a metal with clinical antineoplastic activity, is known to inhibit cellular iron uptake and iron-dependent DNA synthesis. Little information exists regarding the efficacy of gallium in combination with other agents. Since alpha-interferon (IFN-alpha) can modulate the action of certain chemotherapeutic drugs, we examined its influence on the growth inhibitory effects of gallium in CCRF-CEM cells. IFN-alpha and gallium as single agents had only minimal to moderate antiproliferative effects. In combination, however, both drugs synergistically inhibited cell growth, causing cell death accompanied by DNA fragmentation. At lower concentrations (120 microM), gallium inhibited cellular iron uptake but did not increase transferrin receptor expression, nor did it block cellular proliferation. The addition of IFN-alpha to this concentration of gallium significantly increased the gallium-induced block of iron uptake, resulting in an increase in transferrin receptors and an inhibition of cell growth. In contrast, IFN-alpha did not enhance the effects of the iron chelator deferoxamine on iron uptake or cell growth. Our studies suggest that gallium and IFN-alpha synergistically inhibit DNA synthesis through a mechanism that includes inhibition of cellular iron uptake and depletion of intracellular iron below the critical level needed to maintain DNA synthesis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

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.

Alloys↗