Radioimmunotherapy: potential as a therapeutic strategy in non-Hodgkin's lymphoma.

Lymphomas are the fifth most common malignancy in the United States and are increasing in incidence. Despite being among the most responsive malignancies to radiation and chemotherapy, the majority of patients relapse or have progressive disease. Monoclonal antibodies (MAbs) directed at cell-specific surface antigens have been useful in the diagnosis of lymphomas and, more recently, the therapeutic mouse-human chimeric MAb rituximab has demonstrated effectiveness in B cell lymphomas. Conjugating MAbs to radionuclides is a strategy for improving the efficacy of MAb lymphoma therapy by delivering radiation in close proximity to the tumour (radioimmunotherapy or RIT). In addition, the low dose rate of the delivered radiation may exert a greater antitumour activity than an equivalent dose of conventional external beam radiation. The antigenic targets for MAb therapy have included CD20, CD22, HLA-DR, and B cell idiotype. Radionuclides that have been used include iodine-131, yttrium-90, and copper-67; there are relative merits and disadvantages to each source of radiation. Clinical studies to date have focused on relapsed and refractory patients with both indolent and aggressive lymphomas, although more recent studies have included previously untreated patients with indolent lymphoma. Radioimmunoconjugate has been delivered as either single or multiple doses. Response rates have varied widely, dependent on the patient population and the response criteria. Of note, complete responses can be achieved in this typically refractory patient group. Toxicities have generally consisted of mild infusion-related nausea, fever, chills, and asthenia. Neutropenia and thrombocytopenia are the dose-limiting toxicities and have prompted the incorporation of autologous stem cell support as a means of achieving dose escalation. To date, RIT has been delivered to highly selected patients in relatively few centres with requisite equipment and specialised personnel. In addition to these requirements, cost is likely to be a barrier to widespread use. The combination of RIT with chemotherapy at conventional or high dose, or with biological agents is a fertile area for investigation. The potential of RIT in the treatment for lymphomas will be defined only by well designed comparative prospective clinical studies.

Prevention of microvascular thrombosis by topical application of recombinant tissue factor pathway inhibitor.

Tissue factor pathway inhibitor is a naturally occurring protein inhibitor of factor X and the tissue factor-factor VII complex of the extrinsic pathway of coagulation. The potential of tissue factor pathway inhibitor as a topical antithrombotic agent was evaluated in a rabbit model of thrombosis that combined intimal injury, anastomosis, and a twisted pedicle. In 207 rabbit ears, a near-complete amputation was performed, preserving the central ear artery and vein. The central ear artery was transected, the intima was removed mechanically over a 1-cm length, the artery was anastomosed, and the ear was twisted 360 degrees, wrapping the intact vein around the artery. Before recirculation, the lumen was irrigated on a blinded, randomized basis with either hirudin (100 or 500 units/ml), heparin (50 or 100 units/ml), tissue factor pathway inhibitor (10, 40, 125, or 250 microgram/ml), heparin and tissue factor pathway inhibitor together, or vehicle (control). Upon arterial reflow, the ears were observed for 7 days. Patency rates after 7 days were as follows: hirudin, 30 and 55 percent; heparin, 43 and 50 percent; tissue factor pathway inhibitor, 75 and 90 percent; heparin and tissue factor pathway inhibitor, 75 percent; and vehicle, 6 percent. The higher concentrations of tissue factor pathway inhibitor led to significantly higher patency rates than heparin, hirudin, or control solutions. Electron microscopic evaluation of specimens irrigated with gold- labeled tissue factor pathway inhibitor revealed the inhibitor bound to the injured intimal surface for at least 3 days postoperatively. Coagulation studies showed no change in the clotting profile upon intravascular infusion with tissue factor pathway inhibitor even at the highest dose used topically. We conclude that tissue factor pathway inhibitor is a more effective topical antithrombotic agent than either heparin or hirudin.

Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit.

Lipoprotein-associated coagulation inhibitor produces feed-back inhibition of tissue factor (tissue thromboplastin)-induced coagulation in the presence of factor Xa Recombinant lipoprotein-associated coagulation inhibitor (rLACI) was tested for its ability to modify thromboplastin-induced intravascular coagulation in a rabbit model that allows monitoring of iodine-125 fibrin accumulation/disappearance in the lung and sampling of blood for the measurement of coagulation parameters. Infusion of thromboplastin into the rabbit caused a rapid increase of radioactivity over the lungs, possibly due to the accumulation of 125I fibrin in the lungs, followed by a rapid decline of radioactivity, suggestive of removal of fibrin from the lungs. Thromboplastin also caused a rapid decrease of systemic fibrinogen that was accompanied by a lengthening of the activated partial thromboplastin time and prothrombin time. The effect of coinfusion of rLACI with thromboplastin or bolus injection of rLACI before thromboplastin infusion was studied. At a high dose of rLACI (800 micrograms/kg body weight), the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed. The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened, possibly due to the presence of thromboplastin in circulation. The thromboplastin-induced radioactivity increase over the lungs was not completely suppressed by lower doses of rLACI (135 to 270 micrograms/kg body weight), but these doses of rLACI prevented systemic fibrinogen decrease. At a bolus dose of 23 micrograms/kg body weight, rLACI provided 50% protection of the fibrinogen consumption (fibrinogen decreased to 82% compared with 65% in rabbits treated with thromboplastin alone). These results show that rLACI is effective in the inhibition of thromboplastin-induced coagulation in vivo.

Crystallization of a chymotrypsin inhibitor from Erythrina caffra seeds.

Crystals of a chymotrypsin inhibitor from Erythrina caffra seeds have been grown out of lithium sulfate, by the hanging drop method of vapor diffusion. The crystals belong to the rhombohedral space group R32, with a = 67.2 A and alpha = 99.4 degrees, and diffract to 3 A resolution.