A new approach to the therapy of cancer based on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2

A new approach to cancer therapy has been developed based on the adoptive transfer of autologous lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (IL-2). Forty-one patients with advanced cancer who have failed all standard treatments were treated in this experimental protocol. Fourteen patients experienced an objective regression of cancer, including one patient with metastatic melanoma who underwent a complete regression. Objective responses were seen in patients with colorectal cancer, renal cell cancer, melanoma, and lung adenocarcinoma. The sites of tumor regression included subcutaneous tissue, lung, and liver. The major side effect of therapy resulted from the administration of high-dose IL-2 and was manifested primarily as fluid retention, resulting in a generalized capillary permeability leak syndrome. This approach to adoptive immunotherapy represents a promising approach to the therapy of patients with metastatic cancer. Attempts to increase the potency and decrease the toxicity of therapy and extend this treatment to patients with smaller tumor burdens are in progress.     

Cyclic nucleotides and suppression of follicle-stimulating hormone release by inhibin

The relative roles of the cyclic nucleotide messengers cAMP and cGMP in the suppression of follicle-stimulating hormone (FSH) secretion in response to inhibin (IBN) were assessed employing rat gonadotropes in monolayer culture. While exposure of cells to gonadotropin-releasing hormone (GnRH) induced a significant increase in the amounts of both FSH and luteinizing hormone (LH) released into the culture medium, these responses were dampened by the administration of IBN (in porcine follicular fluid). Addition of cGMP to the system failed to restore FSH release, while cAMP restored basal FSH release. Modulation of nucleotide metabolism with theophylline, sodium nitroprusside, and a protein kinase inhibitor failed to overcome the IBN-induced suppression of FSH release. The cellular content of calmodulin increased in response to GnRH, a response antagonized by IBN. Cellular levels of cGMP were also increased by GnRH, but this response was unaltered by IBN. The administered drugs all failed to reverse these effects of IBN. These data indicate that the IBN-induced suppression of FSH release is not dependent upon the cyclic nucleotides cAMP and/or cGMP. However, a role in the maintenance of basal FSH synthesis and release for cAMP is indicated.     

Late regrowth of pituitary adenomas after irradiation and/or surgery. Hazard function analysis

A retrospective analysis was performed on all patients with pituitary adenomas treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, St. Louis, Missouri. Of 210 patients treated from April 1954 through December 1982, 70 were treated with radiotherapy alone (RT), 121 received immediate postoperative RT (2 to 6 weeks), and 19 received RT following surgical failure. The mean follow-up time from the date of diagnosis for those patients alive at the time of last follow-up was 13.0 years (range, 3.0 to 30.0 years). Actuarial progression-free survival was analyzed up to 30 years. The 10-, 20-, and 30-year progression-free survival was 80.5%, 73.5%, and 73.5% for those patients treated with irradiation alone and 92.8%, 71.2%, and 44.0% for those treated with immediate postoperative irradiation. The median time to first failure from initial diagnosis by original treatment was 3.8 years for surgery alone, 4.2 years for RT only, and 10.2 years for surgery plus postoperative RT. Analysis for risk of recurrence per 5-year interval was performed using a hazard function analysis. The risk of recurrence after radiotherapy alone was greatest during the first 5-year interval after treatment and decreased to zero by 20 years. However, the risk of recurrence after primary surgery and postoperative radiotherapy revealed an increasing risk for recurrence up to 30 years after treatment. The concept of "cure" for pituitary adenomas requires extended follow-up.     

Platelet inhibitory effects of CRP preparations are due to a co-isolating low molecular weight factor.

We previously reported that C-reactive protein (CRP), an acute phase reactant, inhibits platelet activation through an effect upon a factor(s) critical to ADP-mediated secondary wave platelet aggregation but independent of a direct effect upon platelet contractile elements. However, a role for an accessory factor in this inhibitory effect became of concern because of an inconsistency in the effects of CRP preparations upon the platelet: inhibition was lost upon storage and CRP preparations differed, on a weight basis, in inhibitory capacity and sensitivity to the presence of the CRP ligand C-polysaccharide (CPS(. The studies presented herein were thus intended to assess whether an accessory factor was involved in the inhibition of platelet activation observed with CRP. We report that the activity of the inhibitory CRP preparations resulted from association with a low molecular weight factor (LMF) with an apparent nominal molecular weight of 8300-12,500 and an A280:A260 ratio of approximately 0.4. Purified CRP did not inhibit platelet responsiveness but CRP with associated LMF (CRP-LMF) did. Moreover, the inhibitory capacity of CRP-LMF but not LMF was substantially reversed in the presence of CPS. These studies indicate that the platelet inhibitory properties of CRP preparations result from and are contingent upon the presence of a co-isolating low molecular weight factor.     

Defibrination with ancrod in experimental chronic immune complex nephritis

The role of fibrin deposition in experimental (crescentic) nephritis in rabbits, due to chronic immune complex deposition induced by BSA, has been studied. Fibrin deposition was prevented and in such animals crescent formation inhibited, suggesting that, as in experimental nephritis due to anti-GBM antibodies, fibrin deposition plays a major pathogenetic role in epithelial cell proliferation. However, in defibrinated animals, mesangial and endothelial cell proliferation, polymorpho-nuclear leucocyte infiltration and impairment of renal function could still occur. These studies are further evidence that defibrination may be of benefit in the treatment of rapidly progressive glomerulonephritis in man.     

Tolerance in TCR/Cognate Antigen Double-Transgenic Mice Mediated by Incomplete Thymic Deletion and Peripheral Receptor Downregulation

Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed with transgenic mice expressing the cognate antigenic protein under the control of the H- 2K^b promoter. Double-transgenic mice show negative selection of thymocytes at the CD4⁺8⁺TCR¹⁰ to CD4⁺8⁺TCR^hi transition stage. A few CD8 T cells, however, escape clonal deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can develop low but detectable levels of antigen-specific cytotoxic function after stimulation in vitro in the presence of IL-2.     

Isolation of a DNA fragment which complements glutamine synthetase deficient strains ofS. pombe

Summary From a gene bank ofS. pombe DNA, a 5.6 kb clone was isolated which complemented mutants defective in glutamine synthetase (GS) activity. Sub-cloning fragments of this 5.6 kb clone showed that the complementing activity was localised in a 1.6 kb HindIII-Aval fragment and a partial DNA sequence revealed an open reading frame preceded by TATA sequences and a TGACTA sequence. Plasmid constructs carrying up to 3.4 kb of DNA used to transformgln ⁻ strains gave transformants which showed a wide range of GS activity, in some cases 100 times the wild-type level. These constructs identify DNA sequences lying downstream from the putative coding sequence which have effects on the total amount of enzyme activity, but do not affect the control imposed by the nitrogen source on which the cells are grown.