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Biomedical subjects

W Kreis

Publications and source records attributed to W Kreis.

At least 91 records · Page 5Linked to original sources
PubMed1978

Methionine requirement and replacement by homocysteine in tissue cultures of selected rodent and human malignant and normal cells.

An absolute methionine requirement for cell growth in culture was observed in four experimental rodent neoplasms, namely, P815/ara-C, L1210, lymphoma 5178Y, and Walker 256. Normal human fibroblast (F-136-35-56) and the human malignant cell lines HeLa and mammary adenocarcinoma (AlAb) cells in culture showed equal growth in 0.1 mM L-methionine or 0.1 to 0.4 mM DL-homocysteine. A human pancreas adenocarcinoma (Capan-1) had somewhat more stringent requirements for DL-homocysteine, whereas a human lung adenocarcinoma (A-549) responded poorly, and a human acute lymphoblastic leukemia (CCRF-HSB-2) responded not at all to equimolar or excess DL-homocysteine in the absence of L-methionine. These differences in requirement for methionine and the ability or inability to replace methionine by homocysteine indicate that a general discrimination between benign and malignant tissues on the grounds of their methionine requirement is not possible for human cells.

Animals↗
PubMed1977

Extraction and analytic procedures for cytosine arabinoside and 1-beta-D-arabinofuranosyluracil and their 5'-mono-, di-, and tri-phosphates.

A qualitative and quantitative comparison of perchloric acid (PCA) and trichloroacetic acid (TCA) extraction procedures of biologic material containing cytosine arabinoside (Ara-C) and 1-beta-D-arabinofuranosyluracil (Ara-U) and their biologic 5'-phosphate derivatives revealed definite superiority of the PCA procedure over the TCA procedure. High-pressure liquid chromatography provides rapid and accurate quantitative and qualitative separation of both Ara-C and Ara-U and their 5'-mono-, di-, and tri-phosphates (mu Bondapak NH2 column), or their 5'-mono-, di-, and tri-phosphates without nucleosides (ABX Permaphase columns).

Animals↗
PubMed1977

Physiologic disposition of cytosine arabinoside and its derivatives in man.

Enzymatic and clinical pharmacologic studies indicate that 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine (AAFC) is relatively resistant to enzymatic deamination and is not phosphorylated but slowly releases 1-beta-D-arabinofuranosyl-5-fluorocytosine. The latter is deaminated rapidly to 1-beta-D-arabinofuranosyl-5-fluorouracil. After iv injection of labeled cytosine arabinoside (Ara-C), 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine, and AAFC into patients, radioactivity appears in substantial amounts and persists for a prolonged time in the saliva. AAFC slowly penetrates into the cerebrospinal fluid, reaches significant levels, and is retained there for a long time. Ara-C, due to rapid deamination in plasma, does not provide sustained levels of Ara-C in the cerebrospinal fluid. It is likely that this difference between AAFC and Ara-C is due to reduced polarity of the former compound.

Administration, Oral↗
PubMed1977

Tetrahydrouridine: Physiologic disposition and effect upon deamination of cytosine arabinoside in man.

[14C]-tetrahydrouridine (THU), a strong inhibitor of cytidine (CR) deaminase, was, after iv administration, rapidly and quantitatively cleared from the blood with a plasma half-life of about 1 hour. The main pathway of excretion was through the kidneys: most of a dose of 50 mg/kg was excreted within 12 hours and excretion was essentially complete within 48 hours. Oral administration of the same dose revealed absorption of about 10% from the gastrointestinal tract. THU at 10, 25, and 50 mg/kg given 15 minutes before [3H]-cytosine arabinoside (ara-C) at a dose of 0.003 mg/kg produced about a two fold increase in ara-C blood levels at all times measured from 5 minutes to 4 hours, with only slight increases in the half-life of ara-C. A dose-related effect of THU upon the deamination of ara-C was obvious only during the time from 15 minutes to 1 hour after the injection of 3H-ara-C. The inhibitory effect of THU upon CR deaminase was also reflected in a considerably increased ratio of ara-C/uracil arabinoside in the urine.

Administration, Oral↗
PubMed1977

Combinations of tetrahydrouridine and cytosine arabinoside in mouse tumors.

Thirteen experimental mouse neoplasms were tested by cytidine (CR)-deaminase and deoxycytidine (dCR)-kinase levels. Four neoplasms, Sarcoma T241, Adenocarcinoma E0771, Lewis lung carcinoma (LL), and Sarcoma 180 Japan (S180J), considered to have high deaminase and sufficient dCR-kinase activities, were tested in vivo for combination chemotherapy with cytosine arabinoside (ara-C) and the CR-deaminase inhibitor, tetrahydrouridine (THU). THU did not significantly improve the growth inhibition of ara-C in a wide range of combinations in T241, E0771, LL, and the solid form of S180J, but more than doubled the survival time of the S180J ascites-bearing animals. Toxicity in the form of weight loss and toxic deaths was observed in some but not all groups, especially at high dosages of ara-C and THU. Tissue distribution of [3H]-ara-C and [14C]-THU in T241-bearing mice revealed an accelerated clearance of ara-C-derived radioactivity under the influence of THU in the tumor and five host tissues, but not in the small intestines. With the exception of the small intestines, clearance of THU-derived radioactivity was faster in all tissues studied compared to the clearance of [3H]-ara-C-derived radioactivity. Intracellular CR-deaminase levels were inhibited significantly, ie, dose dependent, in tumor and host kidney after a single ip injection of THU to E0771--bearing mice. In the solid S180J, with or without simultaneous ip administration of THU, [3H]-ara-C was not converted to 5'-di- and tri-phosphates at all. In mice bearing the ascites form of S180J, [3H]-ara-C was extensively converted to ara-C 5'-di- and tri-phosphates. THU increased both overall ara-C-derived radioactivity and the relative amounts of ara-C 5'-di- and tri-phosphates.

Adenocarcinoma↗
PubMed1976

Separation of 5'-mono-, di- and triphosphates of 1-beta-D-arabinofuranosylcytosine and of 1-beta-D-arabinofuranosyluracil by thin-layer and high pressure liquid chromatography.

The separation of all the 5'-mono-, di- and triphosphates of ara-C and ara-U by thin-layer (TLC) and high pressure liquid chromatography (HPLC) is described. Whereas for the TLC two different systems are necessary, HPLC allows a rapid separation of all the nucleotides with high resolution, reproducibility, and sensitivity within 15 minutes. An example of an HPLC separation of ara-C and ara-U nucleotides derived from a biological sample is presented.

Arabinofuranosyluracil↗
PubMed1975

Physiological disposition of 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine in humans.

[2-14C]-2,2'-Anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine ([14C]AAFC) was given to 7 patients i.v. and to 3 patients p.o. at doses of 2 or 20 mg/kg. After i.v. administration of [14C]AAFC, 20 mg/kg, maximum plasma levels of up to 42.5 mug [14C]AAFC equivalents per ml of plasma occurred. A rapid exponential decrease of the radioactivity resulted in an initial half-line of 0.5 to 1.5 hr for the first part and a half-line of 8 to 24 hr for the second part of the curve. Most of the radioactivity was unchanged starting material. In plasma, 1-beta-D-arabinofuranosyl-5-fluorocytosine was found for only a short time and at low levels after i.v. injection. Its deamination product, 1-beta-D-arabinofuranosyl-5-fluorouracil (AFU), too, showed up in minor quantities. A small amount of 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorouracil was also detected. Administration p.o. of the 14C-labeled drug (2 mg/kg) resulted in the slow appearance of radioactivity in plasma. It peaked at 6 to 18 hr and slowly disappeared with a half-life of 12 to 18 hr. In a fasting patient, [14C]AAFC, 20 mg/kg, administered p.o. resulted in its rapid absorption into the bloodstream and in elevated levels in plasma for 48 hr. The unchanged drug and AFU were the predominant substances identified in plasms. Radioactivity after i.v. injection was found primarily in urine; only small amounts were recovered in expired air (to 2.4%) and traces were found in feces. The predominant urinary excretions product was the unchanged drug (average, 79%). The rest was AFU (average, 12.4%), 1-beta-D-arabinofuranosyl-5-fluorocytosine (average, 3.9%), and 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorouracil (average, 1.9%). After p.o. administration of the labeled drug, the calculated absorption was 32%. Urine contained about 50% unchanged drug and 40% AFU; the remainder was composed of 1-beta-D-arabinofuranosyl-5-fluorocytosine and the deaminated anhydro compound, 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorouracil. The rate of excretion in the urine was slow. In general after both i.v. and p.o. administration, spinal fluid contained considerably less radioactivity than plasma at shor intervals after the administration. At longer intervals after i.v. and p.o. administration, spinal fluid contained comparable or even considerably higher levels of radioactivity when compared to the levels in plasma. Autopsies performed 6 to 25 days after i.v. or p.o. drug administration revealed that radioactivity remained in kidney, spleen, small intestine, liver, and lung.

Administration, Oral↗