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At least 19 recordsLinked to original sources
PubMed1975

Effect of deoxyuridine coadministration on toxicity and antitumor activity of fluorouracil and floxuridine.

The addition of deoxyuridine (UDR) to fluorouracil (FU) or floxuridine (5-fluoro-2' deoxyuridine) (FUDR) produced a substantial increase in their toxicity in BDF1 mice. Antitumor assays using sarcoma 180 tumor-bearing mice showed a concomitant increase in tumor growth inhibition for the nucleoside-drug combination over identical doses of the single drug. However, no significant increase in antitumor activity with the combination treatment was demonstrated when equitoxic doses were given. Additional support for the therapeutic equality of the single and combination drug regimens was the similarity of the therapeutic indexes for each treatment regimen involving either fluorouracil or floxuridine. The results suggested that any therapeutic benefit achieved with the combination therapy could be duplicated with either fluorouracil or floxuridine at a higher dose.

Animals↗
PubMed1977

Liposomal entrapment of floxuridine.

Floxuridine was found to have an apparent initial entrapment within negatively charged sphingomyelin liposomes about three times higher than its parent, fluorouracil. The drug also diffused out of the liposomes at a much lower rate than fluorouracil. Substitution of lecithin for sphingomyelin destroyed the effect. Liposomal entrapment may provide enhanced stability and decreased toxicity of floxuridine, permitting wider therapeutic utilization of pyrimidine nucleosides.

Chemistry, Pharmaceutical↗
PubMed1976

5'-nucleotide phosphodiesterase activity of floxuridine-resistant mouse glioma.

In tissue culture experiments, cells derived from glioma 26, a transplantable tumor of C57B1/6 mice, were sensitive to both floxuridine (5-fluorodeoxyuridine) and 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl)phosphate, an enzyme-mediated drug activated by 5'-nucleotide phosphodiesterase. When these compounds were tested on the tumor in animals at a level of 5 mg/kg for 5 days, tumor growth was inhibited approximately 20% by both compounds. When higher levels of 5-fluorodeoxyuridine, 100 mg/kg four times weekly throughout the lifespan of the mouse, were given, the tumor, although inhibited at first, developed resistance and continued to grow until it killed the animal. Phosphodiesterase levels in the tumor rose as the tumor grew. On the other hand, thymidine kinase levels dropped as anticipated from the known 5-fluorodeoxyuridine-resistant hepatoma tissue culture data. This enzyme pattern was maintained in transplantable mouse glioma lines established from the resistant tumors. One of these lines, tested at a level of 5 mg/kg for 5 days, showed no response to 5-fluorodeoxyuridine but was still sensitive to 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl) phosphate. These experiments, therefore, offer a model system and a rationale for the design and study of more compounds that could be activated by the enzyme phosphodiesterase. Such compounds might be used alternatively when resistance to 5-fluorodeoxyuridine develops, a common clinical experience in the use of this anticancer drug.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1978

GLC determination of floxuridine in plasma using a thermionic nitrogen detector.

A specific GLC method was developed for the determination of floxuridine in plasma using the thermionic nitrogen detector. The method involves the isolation of the compound and internal standard from plasma on a strong anion-exchange column at pH 10, followed by elution with 0.3 M acetic acid in methanol. The eluate is evaporated to dryness, and the residue is dissolved in dimethyl sulfoxide and permethylated with potassium tert-butoxide and methyl iodide. The permethylated compounds are reextracted from the reaction mixture with cyclohexane-methylene dichloride (9:1). The organic solution is evaporated to dryness, the residue is dissolved in ethyl acetate, and an aliquot is analyzed by GLC on a 3% OV-17 column. The extraction recovery from spiked plasma was 93.2 +/- 2.1% (SD), whereas linearity for the overall procedure was in the 0-1-microgram/ml range. The detection limit of the thermionic nitrogen detector was 50 ng/ml. The within-run and within days precision (CV) were 4.0 and 6.2%, respectively, at 300 ng/ml.

Chromatography, Gas↗
PubMed1975

Clinical management of advanced gastrointestinal cancer.

Although advanced gastrointestinal cancer is the most commonplace problem encountered by the medical oncologist, this group of diseases has proved exceedingly resistant to past chemotherapy efforts. 5-Fluorouracil (5-FU), accepted by some as standard treatment, had provided only infrequent, incomplete, and fleeting antitumor effects, which are probably more than counterbalanced by its gastrointestinal, mucocutaneous, and hematologic antihost effects. There is no evidence that any manipulation of route or schedule of administration provides any improvement in the therapeutic ratio of 5-FU. There is no evidence that this drug contributes to patient survival when used at any stage of any type of gastrointestinal carcinoma. The search for alternative single drugs to 5-FU has been disappointing. The nitrosoureas and Mitomycin C produce occasional regressions, but they do not match the meager effectiveness of 5-FU; and they, in addition, present the difficult problem of cumulative bone marrow suppression. Recent trials with combination regimens have given some indication that the long stalemate in chemotherapy of gastrointestinal cancer may be breaking. Substantial improvements in frequency of tumor regression have been recorded for gastric carcinoma with combinations of 5-FU and BCNU, 5-FU and methyl CCNU, and 5-FU, Mitomycin C, and cytosine arabinoside; for colorectal carcinoma, with the combination of 5-FU, methyl CCNU, and vincristine; and for carcinoid tumors and islet cell carcinomas, with the combination of 5-FU and Streptozotocin. There are also suggestion that such combination chemotherapy with response rates in the 30 to 50% range may produce increased survival when compared to the untreated patient and patients treated with single-drug regimens. While the accomplishments of chemotherapy for the gastrointestinal cancer patient remain less than spectacular there is nevertheless realistic hope that a respectable contribution can now be made to multidisciplinary efforts applied at a stage of disease with minimal tumor burden.

Adenoma, Islet Cell↗
PubMed1975

The chemotherapy of urologic cancer.

A review of the status of evaluation of chemotherapeutic agents in the urologic malignancies reveals a largely neglected area of investigation. Except for testicular carcinomas, which are highly responsive to drug therapy, active agents have not been clearly established for the other urogenital tumor sites. Published information and data on file in the Cancer Therapy Evaluation Program of the National Cancer Institute are reviewed, and studies currently in progress are outlined. Adequate clinical testing of the standard antitumor agents that are active against other human malignancies should receive high priority in future therapeutic trials in urologic cancer.

Adenocarcinoma↗
PubMed1977

Thymidine labeling index of human breast carcinoma. Enhancement of in vitro labeling by 5-fluorouracil and 5-fluoro-2'-deoxyuridine.

Inhibitors of thymidylate synthetase, 5-fluoro-2'-deoxyuridine (FUDR) and 5-fluorouracil (FU), enhanced in vitro thymidine labeling of human breast carcinoma cells. Their use resulted in an increase in the measured thymidine labeling index (TLI) of breast carcinomas by increasing detectability of labeled nuclei in autoradiographs. The TLI was measured with FU or FUDR enhancement in primary breast carcinomas from nine women younger than age 50, and from 30 women 50 years or older. The mean and geometric mean TLI were 8.0 and 6.3 respectively for the younger group, and 4.0 and 2.8 respectively for the older group. Similar significant age-associated differences were noted in a series of 133 TLI measurements without FU or FUDR. The TLI was not significantly correlated with primary breast carcinoma size or number of axillary nodal metastases. The capacity to form axillary metastases must be related to factors other than the rate of cell replication in breast carcinomas.

Breast Neoplasms↗
PubMed1977

Factors related to survival following resection for gastric carcinoma: analysis of 903 cases.

This report is based on 903 patients with resections for gastric carcinoma between October 1957, and July 1969, entered in controlled trials of adjuvant therapy with Thio-TEPA and FUDR. Neither Thio-TEPA nor FUDR, as administered, prolonged survival. The extent of disease at the time of curative surgery is related to survival for the first 36 months postoperatively. Involvement of lymph nodes, resection of the esophagus, and serosal penetration are predictive of recurrence up to 36 months. There appear to be three groups of patients: 1) Cured (26%); 2) Slowly growing tumor--23% (median survival, 25 months); and 3) Rapidly growing tumor--51% (median survival, eight months). The absence of blood-vessel invasion, lymphatic invasion, lymph-node involvement, and serosal penetration characterize those patients in Group A.

Adult↗
PubMed1978

A combined treatment approach to management of hepatic metastasis.

Forty-eight patients with liver metastases were treated at Rhode ISland Hospital in a nonrandomized sequential manner between January 1972 and June 1977. Eight received 5 FUDR hepatic artery infusion, 14 hepatic irradiation, and 25 were planned for combined intra-arterial chemotherapy plus total hepatic irradiation. Those patients who successfully completed induction treatments had a median survival in the radiation only group of 140 days, in the intra-arterial chemotherapy group 270 days, and in the combined group 376 days. Hepatic radiation when combined with chemotherapy was well tolerated. Primary tumor site, disease duration, and degree of abnormality of liver function had no relationship to the response to treatment. The pretreatment performance level of the patient as determined by the Karnofsky Performance Index gave the best indication for potential response to combined therapy. Based on the results of this treatment and the reports of other series, it appears that the combination of intra-arterial 5 FUDR plus hepatic irradiation may offer prolonged and worthwhile palliation to appropriately chosen patients.

Bone Marrow↗
PubMed1979

Cytotoxic drugs and the human adrenal cortex: a cell culture study.

Primary monolayer cultures of nonproliferating adult human adrenocortical cells have been used to screen 18 cytotoxic drugs used in cancer chemotherapy for direct effects on corticosteroidogenesis. None of the drugs tested, with the exception of 5-fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine, showed significant activity at levels compatible with cortical cell viability and/or likely to be encountered during therapy. These two antimetabolites, however, resulted in a slow but long-lived reversible suppression of corticosteroidogenesis in both ACTH- and monobutyryl cyclic AMP-stimulated, as well as unstimulated cultures of human cells. Thus 10 micrograms/ml resulted in less than 80% inhibition after seven days treatment without any evidence of overt cytotoxicity. High-pressure liquid chromatography showed a suppression of all UV-absorbing steroids secreted. Examination of the ultrastructure of the treated cells showed significant changes in mitochondrial morphology, suggesting a possible site of action for the antisteroidogenic effects of 5-fluorouracil. These in vitro results suggest the possibility of adrenal suppression in vivo during long-term or high dose infusion 5-FU chemotherapy.

Adrenal Cortex↗
PubMed1979

Prolonged and continuous percutaneous intra-arterial hepatic infusion chemotherapy in advanced metastatic liver adenocarcinoma from colorectal primary.

Sixty patients with advanced metastatic adenocarcinoma of the liver from a colorectal primary were treated by prolonged and continuous intra-arterial hepatic arterial infusion chemotherapy over a period of time from December 1969 through July 1976. A 10-day course of 5-FU was administered in the hospital, and patients were discharged receiving 5-FUDR by continuous arterial infusion through a chronometric infusion pump. Objective responses of 100% were obtained in 15% of patients, 50% response in 39% of patients, and 25% response in 21% of patients. The median survival from onset of treatment was 8.5 months, 6.9 months, and 7 months, respectively, for 100%, 50%, and 25% responders versus 3.6 months for nonresponders. Survivals from onset of treatment were generally less in those with no disease-free interval. No relationship of response to sex and age was found. Patients previously treated with 5-FU intravenously responded to intra-arterial chemotherapy; 13% had a 100% response, and 54% had a 50% response. No relationship of drug dose to response was observed. Drug toxicity was frequently systemic and mild to moderate. Numerous complications occurred due to the catheter, complete or partial thrombosis occurring in 18.6% and 20.8%, respectively, and 30% of patients had displacement of the catheter. The role of partial arterial occlusion in terms of response and survival may be significant. Future studies should involve comparison of direct surgical placement versus percutaneous placement of catheters.

Adenocarcinoma↗
PubMed1976

Adult thymectomy prevention of the appearance of suppressor T cells which depress contact sensitivity to picryl chloride and reversal of adult thymectomy effect by thymus extract.

Suppressor cells, which depress the passive transfer of contact sensitivity appear in the lymph nodes and spleen of mice injected with picryl sulfonic acid (PSA). These cells produce a soluble suppressor T cell product (s-TCP), and immune lymph node cells incubated in s-TCP fail to transfer contact sensitivity. This paper shows that the appearance of suppressor T cells following the injection of PSA was prevented by adult thymectomy (ATx). ATx also limited the production of s-TCP. However, ATx had no effect on the DNA synthesis which occurs in the lymph nodes of mice injected with PSA. The adverse effect of ATx on suppressor cells was completely reversed by a neonatal thymus graft placed under the renal capsule and partially reversed by grafts given 600 r in vitro and to a limited extent by grafts given 1000 r. The injection of thymus extract also reversed the effect of ATx whereas splenic extract was inactive. It is suggested that the suppressor T cell which depresses contact sensitivity is dependent on the presence of the thymus because it requires a thymus hormone, and not primarily because it belongs to a short-lived population which is rapidly renewed by cells coming from the thymus.

Animals↗
PubMed1978

Differentiation of mouse myeloid leukemia cells is inhibited by a factor from non-differentiating leukemia cells.

Mouse myeloid leukemia cells (MI) were induced to differentiate by a factor(s) (D-factor) in ascitic fluid. An inhibitory activity (I-activity) for the induction of differentiation was present in conditioned medium and lysate of MI cells resistant to the D-factor. The I-activity was non-dialyzable, heat-labile and protease-sensitive. Most of the activity was recovered in the fraction precipitated with 30-50% saturated ammonium sulfate. The fraction inhibited induction of phagocytic activity, migrating activity and morphological changes in MI cells, which are typical properties of differentiated MI cells. Low levels of I-activity were detected in conditioned medium or lysate of MI cells sensitive to the D-factor. The resistant MI cells were sensitized to the D-factor by treatment with a low concentration (5-10 ng/ml) of actinomycin D. The I-activity in conditioned medium of actinomycin D-treated resistant cells decreased with development of sensitivity to the D-factor. These results suggest that production of the I-activity in the resistant cells is closely associated with resistance of the MI cells to the D-factor.

Animals↗
PubMed1975

Control of normal differentiation of myeloid leukemic cells. VI. Inhibition of cell multiplication and the formation of macrophages.

D+ but not D- myeloid leukemic cells can be induced by the appropriate conditioned medium or by serum from endotoxin treated mice, to undergo cell migration in agar, cell attachment to the surface of a Petri dish and differentiation to mature macrophages and granulocytes. Inhibition of cell multiplication by cytosine arabinoside, hydroxyurea, mitomycin C, thymidine, 5-bromodeoxyuridine, 5-iododeoxyuridine, 5-fluorodeoxyuridine or actinomycin D, but not by vinblastine or cycloheximide, induced cell migration, cell attachment to the Petri dish and the formation of macrophages in D+ cells. There was no induction of cell migration or formation of macrophages and a much lower induction of cell attachment in D- cells. The induction of these changes in D+ cells required protein synthesis and the inhibitors showed the same toxicity for D+ and D- cells. The results indicate, that the inhibitors induced specific surface membrane changes in D+ but not in D- cells.

Animals↗
PubMed1975

Incorporation of thymidine and iodeoxyuridine in mammalian cells in vitro.

The incorporation of labelled thymidine (dT) and iododeoxyuridine (IdU) into DNA was studied with tissue culture cells and with normal mouse cells in vitro. The rates of incorporation and the ratio dT/IdU incorporation both varied from one type of cell to another and from one suspending medium to another. Despite the known complexity of the regulation of DNA synthesis, the data for incorporation of exogenous dT and IdU could be fitted reasonably well by a model for single-step enzymic process. Deviations from the theoretical predictions were minimal in the presence of fluorodeoxyuridine.

Binding, Competitive↗
PubMed1976

Increased susceptibility of murine teratocarcinoma cells to Simian virus 40 and polyoma virus following treatment with 5-bromodeoxyuridine.

Cultures of the multipotential stem cell, embryonal carcinoma (EC), of a murine teratocarcinoma were treated with 5-bromodeoxyuridine (BrdU). Within 2-4 days at concentrations of 1-50 mugm/ml of BrdU, there was a marked change in the morphology of cells observed by light and electron microscopy. A comparison of the growth potential showed that for up to four days the BrdU-treated cultures were similar to untreated cultures. When these BrdU-treated cells were infected with Simian virus 40 (SV40) and polyoma virus (Py), there was an increase in susceptibility of the treated cells. The untreated embryonal carcinoma cells were refractory. These results suggest that BrdU modifies the embryonal carcinoma cells to allow infection with two DNA viruses.

Antigens, Viral↗