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PubMed1987

Lack of clinical significance of gallium-67 uptake in non-small cell lung cancer.

To evaluate the clinical significance of tumor Ga-67 uptake, we studied 89 consecutive patients with a potentially resectable non-small cell lung cancer (NSCLC) by performing a whole body Ga-67 scan. For each scintigraphy, an overall Ga-67 accumulation index (T-N) and a volume independent index (T/Nr) were calculated. Both parameters were related to disease extent, response to subsequent treatment and host survival. With the exception of the significant correlations of T-N to both stage of disease and survival-the higher the T-N, the more advanced the disease and the worse the prognosis-no other relationship was found. Based on these findings, we conclude that, in NSCLC at least, gallium uptake is mainly dependent on tumor size and, therefore, of limited practical value.

Adult↗
PubMedDate not supplied

Antitumor activity of gallium and lanthanum: role of cation-cell membrane interaction.

Using the vital dye inclusion method and the radioisotopic study of Ca2+-transport, we have investigated the involvement of the gallium and lanthanum plasma-membrane interaction in the cytotoxic and antitumor characteristics of both cations. The experimental results support the hypothesis that such an interaction is the principal cause of antitumor activity, either through structural changes of the cell membrane or through inhibition of the ATPase pumps.

Adenosine Triphosphatases↗
PubMed1988

Inhibition of leukemic HL60 cell growth by transferrin-gallium: effects on ribonucleotide reductase and demonstration of drug synergy with hydroxyurea.

Cellular requirements for iron during DNA synthesis are related to the increased activity of the iron-containing M2 subunit of ribonucleotide reductase, the enzyme responsible for the reduction of ribonucleotides to deoxyribonucleotides. We have previously shown that transferrin-gallium (Tf-Ga) inhibits cellular iron incorporation. In the present study, Tf-Ga-induced inhibition of HL60 cell growth and upregulation of Tf receptor density was reversed with hemin. Cells exposed to 2 mumol/L Tf-Ga for six hours or longer displayed a diminution in the electron spin resonance (ESR) spectroscopy signal of the tyrosyl radical of the M2 subunit of ribonucleotide reductase. The effect of Tf-Ga on the ESR signal was reversed by hemin. Tf-Ga decreased the incorporation of 14C-adenosine into DNA and decreased intracellular deoxyribonucleotide pools, with the maximum diminution seen in deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) pools. Exposure of cells to combinations of Tf-Ga and hydroxyurea (a known inhibitor of ribonucleotide reductase) resulted in a marked inhibition of cell growth that was consistent with drug synergy. Our studies suggest that Tf-Ga inhibits DNA synthesis through action on the M2 subunit of ribonucleotide reductase and that combinations of Ga and hydroxyurea should be further evaluated in in vivo tumor models.

Cell Division↗
PubMed1987

[Value of leukocyte and gallium scintigraphy in the differential diagnosis of splenic abscess/-infarct].

The authors describe the limited role of non-invasive imaging procedures in the differential diagnosis of splenic abscess versus infarction. Sonography and computed tomography often do not offer any characteristic findings in these splenic disorders. A case is reported as an example. By means of 111 In-labelled leukocyte and gallium-67-scintigraphy exclusion of acute inflammatory processes can be performed with great certainty, and unnecessary surgical interventions can thus be avoided.

Abscess↗
PubMed1987

[Gallium-67 scintigraphic evaluation of primary dilated myocardiopathies in adults].

Myocardiopathy (MCP) is diagnosed by exclusion in patients with congestive heart failure in the absence of lesions of the coronary vessels or cardiac valves. Endo-myocardial biopsies and several cases of clinical improvement under immunosuppressive therapy suggest that it may be due due to an immune mechanism. Gallium-67 is taken up by the myocardium and may be regarded as a scintigraphic marker of myocardial inflammation. It may therefore be used to determine which patients would benefit from immunosuppressants. Our study involved 47 patients (mean age 40.1 +/- 10.2 years) with MCP evidenced by angiography and coronary arteriography. Isotopic ejection fraction (EF) and Ga-67 uptake by the myocardium were evaluated in all cases. A significant Ga-67 uptake was observed in 22 patients, 20 of whom could be divided into two groups: group I received an immunosuppressive treatment (azathioprine plus prednisone); group II did not receive such treatment. A new radionuclide cardiac examination was carried out 5 months after the beginning of treatment. No significant Ga-67 uptake could be detected in either group. Significant improvement of EF was observed in 6 patients of group I and in 2 patients of group II. Four patients had died: 1 in group I and 3 in group II. Thus, a decrease in Ga-67 uptake was noted in all patients 5 months after the initial examination, irrespective of the treatment received, which suggests that this decrease belongs to the natural history of the disease. The effect of immunosuppressive therapy on MCP, therefore, ought to be re-evaluated.

Adult↗
PubMed1988

Mechanisms of gallium-67 accumulation by tumors: role of cell membrane permeability.

The effects of citrate ion on in vitro and in vivo uptake of [67Ga]citrate by tumor cells have been studied. Carrier-free [67Ga]citrate seems to follow the physical diffusion of citrate ions into the cell, and the presence of carrier gallium inhibits that diffusion, reducing considerably its uptake. These results appear to support the hypothesis that increased permeability of tumor cells is the principal cause of [67Ga]citrate accumulation by tumors.

Animals↗
PubMedDate not supplied

Gallium arsenide.

The demand for high-speed devices for a variety of communications and military purposes has resulted in a growing interest in alternatives to silicon, with particular attention to compounds of groups 3 to 5 on the periodic table. Gallium arsenide has proved to be an ideal substrate material for some uses but is associated with unique health hazards.

Animals↗
PubMed1987

Gallium nitrate in prostatic cancer: evaluation of antitumor activity and effects on bone turnover.

Gallium nitrate, an agent known to inhibit bone resorption, was evaluated in patients with bidimensionally measurable hormone-refractory prostatic cancer. The starting dose was 200 mg/m2 iv by continuous infusion over 7 days. Two patients (10%; 95% confidence limits, 0%-22%) achieved short partial remissions of 1 and 6+ months, while seven of 23 (30%; 95% confidence limits, 14%-52%) showed a diminution of bone pain. Serial indices of bone turnover including serum calcium, phosphorus, and urinary hydroxyproline excretion showed a significant decrease at the completion of the infusion which returned to baseline prior to the next cycle. The data suggest the effect on bone was too short to produce consistent improvement. Reasons for the dissociation of pain relief and antitumor activity are discussed.

Adenocarcinoma↗
PubMed1988

Increased delivery of gallium-67 to tumors using serum-stable liposomes.

Gallium-67 chelated to nitrilotriacetic acid was encapsulated in liposomes composed of various phospholipids, and 67Ga delivery potential to the tumor after intravenous injection of these liposomes was examined. Tumor uptake of the liposomes themselves and their stability in the serum were also studied. It was found that liposomes composed of distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, or sphingomyelin with cholesterol (molar ratio of phospholipid:cholesterol, 2:1) could be taken by the tumor effectively and could deliver large amounts of 67Ga to the tumor. They could also give high 67Ga accumulation ratios (tumor to the other tissues). The study of liposomal stability in the serum suggested that the marked 67Ga accumulation in the tumor resulted from the serum stability of the liposomal bilayer, i.e., the stable liposomes in the blood circulation could reach the tumor in large quantities after i.v. injection. These observations indicate that liposomes with an appropriate lipid composition may be an excellent tool to accumulate 67Ga in tumors.

Animals↗
PubMed1988

Gallium-67 breast uptake in a patient with hypothalamic granuloma (sarcoid).

An unusual case is presented of bilateral breast uptake of [67Ga]citrate in a patient with a hypothalamic granuloma in the absence of galactorrhea is presented. A possible mechanism for this incidental finding is elevated prolactin levels, as other causes of gallium breast uptake such as drug therapy, and intrinsic breast disease, were not present.

Adult↗
PubMed1986

Accumulation of indium-111-labeled neutrophils and gallium-67 citrate in rabbit abscesses.

A rabbit abscess model was developed to study the effect of abscess age on the accumulation of indium-111-labeled neutrophils ([111In]N) versus gallium-67 citrate (67Ga). Abscesses 1-2 hr, 6-8 hr, 24 hr, and 7 days old were induced by subcutaneous injection of autoclaved colon contents prior to i.v. administration of either [111In]N or 67Ga. Radioactivity in the abscesses was determined 48 hr postinjection. Accumulation of [111In]N was inversely proportional to abscess age. Seven-day-old abscesses were inconsistently seen on [111In]N scans. In contrast, 67Ga accumulation was not affected by abscess age and all abscesses could be identified on a scan 48 hr postinjection. Scans with [111In]N were clearly superior to 67Ga scans for demonstrating early abscesses. Since 67Ga accumulated to a greater extent than [111In]N in abscesses 7 days old, it may be a superior imaging agent for older abscesses.

Abscess↗
PubMed1987

Inhibition of gallium-67 uptake in melanoma by an anti-human transferrin receptor monoclonal antibody.

The effect of an anti-human transferrin receptor (anti-TFR) monoclonal antibody (MoAb), designated B3/25, and an anti-melanoma antibody, designated 96.5, on the uptake of gallium-67 (67Ga) by tumor was studied. Three groups of six athymic mice bearing a human melanoma were injected via tail vein with (a) 0.55 mg human serum albumin (HSA) (control group), (b) 0.5 mg MoAb B3/25 + 0.55 mg HSA, and (c) 0.5 mg MoAb 96.5 + 0.55 mg HSA, respectively. Twenty-four hours later, each mouse was given an intravenous dose of 5 microCi [67Ga] citrate. Biodistribution of activity (percent injected dose per gram) determined 48 hr after injection of 67Ga showed a 75% decrease in tumor uptake in the group of mice that received B3/25 (anti-TFR MoAb) compared with the control group. In contrast, MoAb 96.5 did not show any effect on melanoma uptake of 67Ga. Histologic findings suggest that the decreased uptake was not due to cellular damage resulting from binding of B3/25 to TFR. The results of this study strongly suggest the involvement of TFR in the in vivo tumor uptake of 67Ga.

Animals↗
PubMed1987

Comparison of gallium-67 versus indium-111 monoclonal antibody (96.5, ZME-018) in detection of human melanoma in athymic mice.

We compared the biodistribution of two radiolabeled, whole, tumor selective monoclonal antibodies [( 111In]96.5, [111In]ZME-018) to 67Ga in nude mice bearing a human melanoma known to express p97 antigen. Localization of gallium was determined 48 hr following i.v. injection. Localization of the radiolabeled antibodies was determined at 3 days and 7 days following i.v. injection. All agents showed more or less similar absolute tumor uptake which varied between 22% and 36% of the injected dose per gram of tumor. Only the tumor uptake of [111In]96.5 antibody at 7 days was significantly lower than the 67Ga uptake at 48 hr. However, uptake in normal tissues was generally higher for both antibodies at 3 and 7 days than for 67Ga uptake at 48 hr. Therefore, the tumor-to-blood ratio for 67Ga was tenfold higher than that for either antibody, the tumor-to-muscle ratio was twofold higher. Bone was the only organ in which the tumor-to-organ ratio was consistently higher with radiolabeled antibody than with 67Ga. The tumor-to-liver and tumor-to-intestine ratios were comparable. Localization of the two tumor selective antibodies was greater than a nonspecific "control antibody" [( 111In]CEA) and change in specific activity from 0.17 mCi/mg to 3.3 mCi/mg did not influence localization. From these animal data it may be anticipated that tumor imaging with [111In]96.5 or [111In]ZME-018 will not be superior to imaging with 67Ga for detection of melanoma.

Animals↗
PubMedDate not supplied

[Gammagraphy with gallium-67 citrate in the diagnosis of pulmonary tuberculosis].

The reception of Gallium Citrate 67 (C. de Ga-67) has been studied in 27 patients with active pulmonary TBC shown bacteriologically. The findings of the gammagraphy with C. de Ga-67 have been compared with those of the simple thorax radiology. We have objectified 96% sensitivity in the examination of the tuberculous lesions by isotopic techniques. These have shown, as well, a high performance in the detection of active tuberculous areas at hiliar, mediatinic and extrathoracic level, greater than that of the simple radiography, as well as to evaluate the activity of apparently residual lesions in the thorax radiography. We conclude that the gammagraphy with C. de Ga-67 is a bloodless method which complements radiology in the diagnosis of activity, extension and location of pulmonary tuberculosis.

Adolescent↗
PubMed1987

Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin.

We quantified pulmonary vascular permeability with positron emission tomography (PET) and gallium-68-(68Ga) labeled transferrin. Six dogs with oleic acid-induced lung injury confined to the left lower lobe, two normal human volunteers, and two patients with the adult respiratory distress syndrome (ARDS) were evaluated. Lung tissue-activity measurements were obtained from sequential 1-5 min PET scans collected over 60 min, after in vivo labeling of transferrin through intravenous administration of [68Ga]citrate. Blood-activity measurements were measured from simultaneously obtained peripheral blood samples. A forward rate constant describing the movement of transferrin from pulmonary vascular to extravascular compartments, the pulmonary transcapillary escape rate (PTCER), was then calculated from these data using a two-compartment model. In dogs, PTCER was 49 +/- 18 in normal lung tissue and 485 +/- 114 10(-4) min-1 in injured lung. A repeat study in these dogs 4 hr later showed no significant change. Values in the human subjects showed similarly marked differences between normal and abnormal lung tissue. We conclude that PET will be a useful method of evaluating vascular permeability changes after acute lung injury.

Animals↗
PubMed1986

Gallium nitrate: the second metal with clinical activity.

Gallium nitrate is the anhydrate salt of the naturally occurring heavy metal. It has demonstrated antitumor activity in a variety of murine tumor models, including Walker carcinosarcoma 256, fibrosarcoma M-89, leukemia K-1964, adenocarcinoma 755, mammary carcinoma YMC, reticulum cell sarcoma A-RCS, lymphoma P1798, and osteosarcoma 124F. Preclinical studies performed in rats, rabbits, dogs, and monkeys showed the dose-limiting toxicity to be renal. The hepatic, pulmonary, gastrointestinal, hematologic, and integumentary systems were also involved. The major route of elimination is the kidneys, with 35%-71% of the infused dose excreted within 24 hours. Three phase I studies suggested the following phase II doses: 700-750 mg/m2 by short infusion, once every 2-3 weeks; 300 mg/m2/day by short infusion for 3 consecutive days, to be repeated every 2 weeks; and 300 mg/m2/day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. The major organ toxicity reported was renal; however, this can be adequately controlled either by hydration and osmotic diuresis or by use of continuous schedule. (Either maneuver appears to allow delivery of the recommended phase II dose with a less than 30% risk of change in serum creatinine.) In limited phase II evaluation, the drug has shown antitumor activity in patients with either refractory lymphomas or small cell lung carcinoma, with total objective response rates of 28% and 11%, respectively. In addition, it has been effective in the treatment of patients with cancer-related hypercalcemia by having an inhibitory effect on calcium reabsorption from bone. Single-agent phase II studies are planned in all major tumor types. Some are already ongoing in patients with genitourinary malignancies (renal, bladder, prostate, testicular), small cell lung carcinoma, and multiple myeloma. Metabolic studies are in progress at Memorial Sloan-Kettering Cancer Center to further elucidate the mechanism or mechanisms of the hypocalcemic effects.

Animals↗
PubMed1987

Specific actions of gallium on norepinephrine-induced tension and associated 45Ca movements in rabbit aortic smooth muscle.

Gallium ion (Ga) dose-dependently (60-360 microM) inhibited contractions induced by norepinephrine (NE, 1 microM) in rabbit aortic (and media intimal) strips, but did not affect contractions elicited with high K+ (80 mM) solution. The initial phasic portion of the NE-induced response was either unaffected or only slightly (less than 10%) reduced, but the tonic portion of the response was inhibited completely by higher concentrations (greater than or equal to 300 microM) of Ga . In resting muscles, the equilibrated (90 min) 45Ca uptake was not altered by Ga (360 microM). Also, 45Ca efflux from either high- or low-affinity Ca++ binding sites was unaltered by Ga . The effects of Ga (360 microM) on 45Ca retained after a subsequent 60-min washout at 0.5 degrees C in an isosmotic (80.8 mM) La solution were also examined. High affinity La -resistant 45Ca released by NE (1 microM) was not altered by Ga . Under conditions favoring low affinity Ca++ uptake, 45Ca retention in control and K+-treated muscles was not changed by Ga , but the additional incremental 45Ca uptake associated with NE (in the presence of high K+) was blocked. Thus, Ga appears to have a selective inhibitory action on NE-associated 45Ca uptake without affecting either resting and high K+-induced 45Ca uptake or that 45Ca fraction released by NE. This action may result from a selective blockade by Ga of receptor-linked Ca++ channels in rabbit aortic smooth muscle.

Animals↗