A pharmacokinetic and phase II study of gallium nitrate in patients with non-small cell lung cancer.

This study investigated the pharmacokinetics and activity of gallium nitrate in non-small cell lung cancer when 700 mg/m2 was given as a 30-min infusion with prehydration every 2 weeks. Gallium was measured in plasma and urine using flameless atomic absorption spectrophotometry, and pharmacokinetics of total and ultrafilterable gallium were calculated. Twenty-five patients with non-small cell lung cancer received 1-12 (median 2) courses of gallium nitrate every 2 weeks. Of 21 patients evaluable for response, 1 partial response was recorded, 4 patients had stable disease. and 16 had progressed. The most serious toxicities were renal impairment and optic neuritis. Hypocalcaemia was recorded in 3 patients. The mean C(max) was 15.2 +/- 3.1 microg/ ml (range 9.5-21.2). Most gallium remained ultrafilterable for the first 10 h, after which plasma protein binding increased, and at 48 h only 11% was present as ultrafilterable gallium. The elimination profiles of both total and ultrafilterable gallium were biphasic, and the distribution phase consisted of ultrafilterable gallium, with a distribution half-life of 1.4 h. Total gallium plateaued at 1.9 microg/ml at between 8 and 12 h, and the estimated elimination half-life was 63 h. The elimination half-life of ultrafilterable gallium was 16.5 h. Inter- and intra-patient variability in pharmacokinetics was minimal. A mean of 50 +/- 14% of the gallium dose was excreted in the urine within 48 h. A short infusion of gallium nitrate achieving high peak plasma concentrations results in little efficacy in non-small cell lung cancer.

Current concepts in radiobiology applied to radiotherapy.

The main research themes in radiobiology are reviewed, with an emphasis on those currently in preclinical or clinical testing. They come largely from recent insights in tumour or cellular biology and include in vivo tumour proliferation kinetics, hypoxic radioresistance, cellular or intrinsic radioresistance, the tumour's abnormal vascular bed. In order to exploit fully their therapeutic possibilities, more specific but clinically-practical methods of gauging each individual tumour's vulnerability may need to be available, so an associated line of research is the development of laboratory assays of biopsied samples to document the relevant tumour characteristics. Imaging is attractive as a relatively non-invasive means of characterising and serially sampling the tumour: this role is not yet well developed but is likely to become much more important.

Human macrophage maturation in vitro: expression of functional transferrin binding sites of high affinity.

Human blood monocytes (mo) when cultured in suspension on hydrophobic teflon membranes undergo terminal maturation to macrophages (MO). Together with the appearance of new lineage-restricted differentiation antigens, mature MO but not blood mo, express transferrin (TF) receptor molecules as detected by immunostaining methods. Here we report that radio- and fluorescein-labelled TF binds to a single class of high-affinity binding sites on MO but not on mo. As mo mature in vitro in the presence of human serum, their receptor numbers increase to about 10(6) per cell, showing an apparent Kd for Fe2TF of approximately 5 nM. These receptor numbers were comparable with our estimates for cultured K 562 human tumor cells, and about 20x greater than reported for human MO cultured in the presence of fetal calf serum. Our MO showed 58Fe uptake comparable with uptake by tumor cells and also exhibited TF-promoted uptakes of 61Ga. The possibility that MO might recycle stored iron through receptor-bound apoTF was not supported by experiments which showed that their Fe2TF receptors had much lower affinity for apoTF (Kd greater than 1 microM) and which could not detect separate high-affinity receptors specific for apoTF. Expression of TF receptors was not substantially altered by treatment with human recombinant interferon-gamma.

The potential accuracy of dual-energy computed tomography for the determination of hepatic iron.

Physical experiments are described which simulated the main practical and technical problems encountered in estimating iron concentrations in liver by dual-energy computed tomography. In aqueous solutions located in an oval water phantom, the presence of Fe at concentrations of 1 and 2 mg/ml was detected and estimated with good accuracy and reproducibility. The main physical problem was that water showed a non-zero dual-energy difference reading whose magnitude varied with location, but this potential error was largely eliminated by measuring the location-specific water values using a technique readily adapted to patient studies. Experiments with pieces of bovine tissue in the same system suggested that the dual-energy response shown by liver tissue may include an Fe-independent contribution, reflecting its organic composition (including fat content): if attributed to Fe, this would correspond to an error less than +/- 1 mg/g wet weight in the evaluation.

Mechanisms of distribution of gallium 67 in mouse tumour hosts.

In several mouse tumour models iron given parenterally not only inhibited the transport of 67Ga by plasma transferrin but also accelerated the binding of 67Ga in tumour tissue, particularly during the first hour after 67Ga injection. By 30 min, the tumour had already attained a high concentration though the 67Ga accumulated was still potentially reversible. With the passage of time equally high 67Ga concentrations were attained in tumour in iron-treated and untreated animals alike, and were maintained high as 67GA was totally cleared from the plasma. Given IV, 125-I-human transferrin was not preferentially bound in tumour whereas in muscle tissue loaded with transferrin, 67Ga was accumulated locally during the immediate post-injection phase and to an enhanced degree in iron-treated animals. A hypothesis is presented which, by drawing attention to the role of extravascular transferrin in binding and presenting 67Ga for cellular uptake, helps resolve the apparent contradictions between in vivo and cell culture findings.

Ga-67 and Fe-59 distributions in mice.

Tissue distributions of i.v.-injected Ga-67 citrate and [59Fe] ferric citrate were measured in normal mice and in lymphoid-tumor hosts. The study arose out of previously reported tissue-culture work showing marked transferrin stimulation of Ga-67 and Fe-59 uptakes by cultured cells from mouse lymphoid tumors. In vivo, however, no obvious correlation was found between Ga-67 and Fe-59 tissue distributions; indeed, Ga-67 showed high affinity for tumor tissue and low affinity for hemopoietic tissues, while for Fe-59 the reverse applied. Taken together, these comparisons of kinetics and distributions for Ga-67 and Fe-59 suggest that a tissue's avidity for Ga-67 is strongly influenced by other factors besides the cell population's capacity for transferrin interactions.

67Ga and 59Fe uptakes by cultured human lymphoblasts and lymphocytes.

Studies with spontaneously proliferating human lymphoblastoid cells have shown that cellular uptake of both 67Ga and 59Fe3+ (as citrates) become appreciably increased with small additions of purified human transferrin to the cultures. In many respects, their uptake responses were broadly similar to those previously reported for cultured mouse lymphoid tumor cells. Studies were also undertaken with cultured human lymphocytes, but transferrin promotion of tracer uptakes could not be detected for these cells. In addition, cellular uptakes for phytochemagglutinin-stimulated cultures were not significantly increased over their unstimulated controls.

Transferrin promotion of 67Ga and 59Fe uptake by cultured mouse myeloma cells.

Radiotracer 67Ga-citrate is used as a tumor-seeking agent in clinical imaging investigations although fundamental reasons for its high uptake in certain malignant lesions remain unexplained. The mechanism by which 67Ga becomes concentrated in tumor cells has been investigated by comparing 67Ga and 59Fe uptake by cultured mouse myeloma cells with particular reference to uptake stimulation by transferrin. Concentrations of human transferrin down to 2 microgram/ml greatly stimulated cellular uptake of both tracers, whereas bovine transferrin proved relatively inactive. The rates of stimulated uptake of both tracers were similar as was their high degree of retention by cells, but their quantitative dependencies on transferrin concentration showed characteristic differences. Pretreatment of human transferrin with saturating amounts of nonradioactive Fe3+ canceled its ability to promote 59Fe uptake, but it had little effect on its promotion of 67Ga uptake. Further increase in the amount of added Fe3+ did cause a progressive depression of 67Ga uptake, but this effect probably relates to the iron distribution in the whole-cell culture system including the fetal calf serum component of cell growth medium. The results suggest that 67Ga and 59Fe reveal different aspects of the interaction of transferrin with cells.

Gallium-67 citrate uptake by cultured tumor cells, stimulated by serum transferrin.

The uptake of the tumor scanning agent 67-Ga citrate by cultured mouse tumor cells wqs greatly enhanced with small additons of certain sera to the culture medium. This stimulation of uptake was due to a macromolecular serum component, provisionally identified with transferrin. The response under optimum conditions was so great as to suggest that the 67-Ga uptake process depends entirely on the action of transferrin. The same mechanism probably operates in vivo and may help explain interesting features of the tracer's tissue distribution, particularly its tumor affinity.