Monoclonal antibodies to a rat colon carcinoma: model for monoclonal antibody therapy of solid tumors.

Tumor progression, lung metastasis, and death occur in tumor-bearing BD IX syngeneic rats in a fashion similar to the course of patients with metastatic colon cancer. In an effort to establish a relevant model for monoclonal antibody (MoAb) therapy of tumors, we generated murine MoAb against DHD/TR, a dimethylhydrazine-induced rat colon carcinoma which has been adapted to cell culture. Murine MoAb 17B10 E4 (E4) reacts with the TR tumor and shows weak immunoperoxidase reactivity with normal rat tissues.

Cytotoxic T lymphocyte-defined epitope differences between HLA-A2.1 and HLA-A2.2 map to two distinct regions of the molecule.

Hemi-exon shuffling and site-directed mutagenesis have been used to determine which amino acid differences between HLA-A2.1 and HLA-A2.2 alter the CTL-defined epitopes on these two molecules.

Identification by site-directed mutagenesis of amino acid residues contributing to serologic and CTL-defined epitope differences between HLA-A2.1 and HLA-A2.3.

Site-directed mutagenesis of HLA-A2.1 has been used to identify the amino acid substitutions in HLA-A2.3 that are responsible for the lack of recognition of the latter molecule by the HLA-A2/A28 specific antibody, CR11-351, and by HLA-A2.

Increased adriamycin levels in hepatic implants of rabbit Vx-2 carcinoma from regional infusion.

Regional infusion chemotherapy for the treatment of primary or secondary hepatic cancer should allow delivery of a higher drug concentration to the tumor with decreased systemic exposure when compared with systemic therapy. Fifteen rabbits, each implanted with two hepatic Vx-2 tumors, were treated with infusion of Adriamycin (3 mg/kg and 7.5 muCi of [14C]Adriamycin) through the hepatic artery (n = 5), portal vein (n = 5), and a systemic vein (n = 5) at 20 mg/min.

Interferon-gamma induces altered oncogene expression and terminal differentiation in A431 cells.

In tumor cell lines in which oncogene expression is abnormal, modulation of the expression of the oncogene (myc, src, or ras) by interferons (IFNs) has been observed concurrently with cell growth inhibition or phenotypic reversion. Oncogene expression has also been reported to vary during the differentiation of several neoplastic cell lines. Treatment of monolayer cultures of A431, a human epidermoid carcinoma cell line, with IFN-gamma resulted in rapid morphological alterations and cell death not seen with either IFN-alpha or IFN-beta.

Tumor and liver drug uptake following hepatic artery and portal vein infusion.

Anatomic dye injection studies of the blood supply of colorectal hepatic metastases suggest that tumors are supplied predominantly by the hepatic artery. Using 13N amino acids with dynamic gamma camera imaging in patients with colorectal hepatic metastases, it has been shown that hepatic artery infusion results in a significantly greater nutrient delivery to tumor compared with portal vein infusion. However, direct measurements of drug levels in tumor following hepatic artery and portal vein infusion in humans have not previously been reported.

Perfusion of colorectal hepatic metastases. Relative distribution of flow from the hepatic artery and portal vein.

The importance of portal circulation in the delivery of drugs and nutrients to colorectal hepatic metastases is controversial. Using 13N (nitrogen 13) amino acids and ammonia with dynamic gamma camera imaging, we demonstrate, for the first time in human beings, a quantitative advantage of hepatic artery compared with portal vein infusion. Eleven patients were studied by hepatic artery injection, five patients were studied by portal vein injection, and two patients had injections through both routes.

Modulation of doxorubicin uptake by epinephrine in the VX-2 carcinoma.

The purpose of regional chemotherapy is to deliver maximal drug concentrations to localized unresectable tumors, to minimize systemic toxicity, and to improve tumor response to treatment. Manipulation of regional blood flow by vasoactive agents could further increase tumor drug levels. This study evaluates the effect of hepatic artery infusion of epinephrine on tumor and liver doxorubicin uptake.

Distribution of fluorodeoxyuridine uptake in the liver and colorectal hepatic metastases of human beings after arterial infusion.

Little is known about drug distribution in tumor metastases or in the liver after hepatic arterial infusion. This information is important for planning strategies to enhance tumor drug uptake and to improve tumor response to therapy. Dye injection studies have demonstrated hepatic tumor vascular supplies in an anatomic manner, but offer no physiologic data.

Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet. II. Reduced toxicity and improved survival using cholestyramine.

The administration of an elemental, chemically defined liquid diet to rats significantly enhanced gastrointestinal toxicity associated with methotrexate administration compared with rats fed a regular chow diet. Chemotherapy induced enteritis is potentially enhanced by the abrasive effect of bile acids on the susceptible cells of the small bowel mucosa. This study evaluated the interactions of methotrexate and cholestyramine in vitro.

Ultrasonographic diagnosis of infected lymphocele after kidney transplantation.

Lymphoceles after kidney transplantation are usually not infected and are drained into the peritoneal cavity, if their size requires treatment. Infected lymphoceles should be drained externally rather intraperitoneally, to avoid peritonitis. Ultrasonographic examinations of 2 febrile patients identified complex echoes that were correctly interpreted as infection within lymphoceles.

Intra-arterial infusion of doxorubicin with degradable starch microspheres. Improvement of hepatic tumor drug uptake.

Regional infusion chemotherapy delivers higher drug concentrations to the tumor than other methods and may decrease systemic drug levels. We evaluated the efficacy of degradable starch microspheres (DSMs) to further increase drug delivery to hepatic tumors. Rabbits implanted with hepatic Vx-2 tumors were treated with hepatic arterial infusion of doxorubicin hydrochloride labeled with carbon 14 with and without DSMs.

Fluorodeoxyuridine uptake by human colorectal hepatic metastases after hepatic artery infusion.

Tumor response rates after hepatic regional arterial chemotherapy infusion vary from 30% to 83% with little explanation for this variability. Drug clearance by the liver and plasma drug kinetics after arterial infusion have been described, but little is known about actual tumor drug uptake. This study measured fluorodeoxyuridine (FUdR) uptake in colorectal tumors metastatic to the liver and correlated these results with radionuclide flow scans and with tumor response to treatment.

Treatment of colorectal hepatic metastases.

Hepatic metastases of colorectal carcinoma are present at diagnosis in 20 per cent of patients and occur within two years in 80 per cent of those which will recur in the liver. Surgical resection of all hepatic disease can confer survival on 20 per cent of resectable patients, but there is no other curative therapy. No systemic drug treatment has been shown superior to 5-FU alone, and the benefit of hepatic artery chemotherapy with FUdR (in contrast with systemic treatment) remains unproved.

Predicting tumor response in patients with colorectal hepatic metastases.

Until now, there has been no reliable means of predicting tumor response to chemotherapy in patients with metastatic colorectal cancer. Using arterial nuclide flow scans as a determinant of tumor response, the degree of tumor perfusion was evaluated in a blinded prospective study. Seventy-three patients with colorectal hepatic metastases received continuous hepatic arterial (N = 52) or systemic intravenous (N = 21) chemotherapy using an implantable pump.

The use of flow cytometry and cell sorting in a human colon carcinoma model.

We investigated the growth characteristics of a human colon carcinoma cell line, WiDr, grown in culture flasks and on chick embryonic skin (CES). WiDr cells labeled in vitro with bromodeoxyuridine (BrdU) and analyzed by combined propidium iodide/Hoechst 33258 fluorescence showed evidence of more BrdU incorporation in early S phase as compared to late S phase. When inoculated on the CES, WiDr cells multiplied and invaded the underlying skin.

Influence of spatial configuration of carcinoma cell populations on the expression of a tumor-associated glycoprotein.

Monoclonal antibody B72.3 was generated using a membrane-enriched fraction of cells from a mammary carcinoma metastasis and has been shown previously to have a high degree of selective reactivity for human breast and colon carcinoma versus normal adult tissues. The reactive antigen has been shown to be a high-molecular-weight glycoprotein complex of approximately 220,000 to 400,000 and is termed tumor-associated glycoprotein 72 (TAG-72).

Measurement of the refolding combination reaction between S-peptide and S-protein.

S-Peptide combines with S-protein during the refolding of ribonuclease S. The kinetics of combination have now been measured by a specific probe, the absorbance (492 nm) of a fluoresceinthiocarbamyl (FTC) group on lysine-7 of S-peptide. pK changes of the FTC group detect both initial combination and later, first-order, stages in folding.

Proliferative variability of endothelial clones derived from adult bovine aorta: influence of fibroblast growth factor and smooth muscle cell extracellular matrix.

Four endothelial cell clones derived from adult bovine aorta were examined with respect to their proliferative characteristics in vitro. Three of these clones, derived in the absence of fibroblast growth factor (FGF), displayed variable basal proliferative rates. One of these non-FGF derived clones grew at a maximal rate which could not be further enhanced with FGF.

Nature of the fast and slow refolding reactions of iron(III) cytochrome c.

The fast and slow refolding reactions of iron(III) cytochrome c (Fe(III) cyt c), previously studied by Ikai et al. (Ikai, A., Fish, W.

Aspartate transcarbamylase of Escherichia coli. Heterogeneity of binding sites for carbamyl phosphate and fluorinated analogs of carbamyl phosphate.

Some preparations of both native aspartate transcarbamylase from Escherichia coli and catalytic subunit have fewer tight binding sites per oligomer for carbamyl-P than the number of catalytic peptide chains. In contrast, the number of sites for the tight-binding inhibitor N-(phosphonacetyl)-L-aspartate does equal the number of catalytic chains in each case. Binding of the labile carbamyl-P was determined using rapid gel filtration, with conversion to stable carbamyl-L-aspartate during collection.

Hypoxia and the energy charge of the cerebral adenylate pool.

A brief period of anoxia in vivo causes a transitory decrease in the size of the adenylate pool in the rat brain. This is probably caused by feedback inhibition by AMP of adenine nucleotide synthesis. Exposing rats to various degrees of hypoxia suggests that the sensitivity of the brain to lack of O(2) results from the brain's limited ability to maintain an adequate energy charge in unfavourable circumstances.

Resting and stimulated respiration in vitro in the central nervous system. Regional distribution and relation to cell density.

1. The respiratory rates in vitro of ten structures of the rabbit brain were measured in the presence of a normal (5mm) and an elevated (50mm) concentration of K(+) ions. The results were expressed on a dry-weight basis and in terms of cell density.

The distribution of cytochrome-oxidase activity in rabbit brain.

1. The cytochrome-oxidase activity in eleven structures of the rabbit brain has been investigated. 2.