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Biomedical subjects

Y M Rustum

Publications and source records attributed to Y M Rustum.

At least 181 records · Page 10Linked to original sources
PubMed1982

Phase I trial and pharmacokinetics of a daily x 5 schedule of 3-deazauridine.

The uridine analog 3-deazauridine has been given to 19 patients in a phase I and pharmacokinetic study. Only mild toxicity was seen at doses less than 1200 mg/m2/day for 5 days. At a dose of 1200 mg/m2/day x 5, leukopenia (mean wbc count nadir of 2650/mm3) was seen in nine of 12 patients and thrombocytopenia (mean platelet count nadir of 47,000/mm3) in five of 12 patients. Nausea and vomiting and oral toxicity were each seen in two patients, and diarrhea and skin toxicity occurred in one patient each. Pharmacokinetic studies indicate a biphasic plasma decay with a beta-half-life of 6.9 hours and urinary excretion, mostly of unchanged drug, as the most important route for drug elimination. A dose of 1200 mg/m2/day x 5 is recommended for phase II studies and great caution is advised in administering the drug in the presence of renal impairment.

3-Deazauridine↗
PubMed1981

The soft agar clonogenicity and characterization of cells obtained from human solid tumors by mechanical and enzymatic means.

A two-step procedure for releasing cells from solid tumors has been applied to specimens of human melanoma, sarcoma, lung, colon, and breast carcinoma. The first population released mechanically has been compared with the population subsequently released enzymatically in tests of dye exclusion, ribonucleoside triphosphate pool sizes, intactness of DNA, and clonogenicity in soft agar. While greater numbers of dye-excluding cells are released in the enzymatic step, and these cells have higher ribonucleoside triphosphate pools and more intact DNA, both populations contain clonogenic cells in approximately equal numbers. Several semisolid media were employed in tests of clonogenicity, and all methods employing an agar underlayer appeared satisfactory and approximately equivalent in cloning efficiency. The methyl cellulose upper layer system facilitated implanting of pooled colonies into nude mice, which resulted in growth in the nude host and marked increase in cloning efficiency when the cells were replanted into soft agar-methyl cellulose plates. A comparison of four different areas of individual tumor specimens was made with cells released enzymatically and measuring cell yield, dye exclusion, ATP pool size, and uptake and metabolism of 5-fluoropyrimidines. Only relatively small variations were seen from one area to the next, with trypan blue exclusion exhibiting the least variation, and metabolism of fluorinated pyrimidines showing the most.

Animals↗
PubMed1981

Chromosomes and causation of human cancer and leukemia. XLIV. A method for chromosome analysis of solid tumors.

Mechanical and enzymatic disaggregation procedures have been utilized for the preparation of materials suitable for chromosome examination of tissues from various kinds of solid tumors. A great number of the cells disaggregated with the latter procedure were observed to attach to the bottom of culture flasks after 2 days in vitro; cells obtained with the former method were not attached. In general, the enzymatic procedure yielded a significantly larger number of viable cells that would undergo mitosis after short term culture and considerably improved the quality of banding as compared to the mechanical method. However, there were no significant differences among the basic karyotypes observed in the cells obtained by the mechanical approach versus those seen following the enzymatic method. This evidence, together with the high success rate of karyotyping in the enzyme-treated preparations, suggest that this should be the procedure of preference for cytogenetic examination of various tumors, particularly where in the past karyotypic examination has been very difficult, e.g., the early stages of tumor development.

Cells, Cultured↗
PubMed1981

Histopathologic technique for the morphological examination of fixed or frozen solid tumor cells in soft agar.

Two simple techniques are described for preparing sections from soft agar colony cultures of tumor cells. Tumor cells grown in soft agar can be frozen, sectioned, and stained and/or fixed in formalin, embedded in paraffin, sectioned, mounted on glass slides, and stained. The methods are simple and reproducible. These cells can be stained with various stains and the staining quality is excellent. The paraffin blocks and microscope slides can be stored for permanent record. The use of these techniques should provide better understanding of the histomorphologic characteristics of neoplastic cells which grow in soft agar and should expand and refine prognosis and diagnosis of malignant tumors.

Agar↗
PubMed1981

Characterization of cells obtained by mechanical and enzymatic means from human melanoma, sarcoma, and lung tumors.

Characterization of cells comprising solid tumors will facilitate the rational design of cancer chemotherapy for individual patients. We have prepared cell suspensions from human melanoma, sarcoma, and lung tumors by thinly slicing the tissue with a microtome and scalpels (mechanical release), followed by treatment with a mixture of collagenase II and DNase I (enzymatic release). This method of disaggregation resulted in two cell suspensions for each tumor specimen, and we characterized these suspensions by assessing their dye exclusion capability, ribonucleoside triphosphate pools, cytological profile and clonogenicity in soft agar. The enzymatic method thus yields cells in addition to those obtainable by a mild mechanical procedure, and these cells are similar in cytological profile and clonogenicity in soft agar to those released mechanically. Furthermore, the enzymatically released population is superior to that released mechanically for purposes requiring large numbers of dye-excluding cells having intact ribonucleotide pools.

Cell Count↗
PubMed1981

Determinants of response to antimetabolites and their modulation by normal purine and pyrimidine metabolites.

Two areas of investigation are discussed: (a) the identification of critical biochemical parameters that may lead to prediction of response of tumor cells to antimetabolites, such as 1-beta-D-arabinofuranosyl-cytosine (ara-C) and 5-FU, and (b) the potential use of normal purine and pyrimidine metabolites in the selective and specific modulation of critical parameters related to ara-C and 5-FU activity. The results presented indicate a strong correlation between ara-CTP formation and retention in leukemic cells and response of animals with leukemias or patients with acute myelocytic leukemia (AML) treated with ara-C or a protocol containing ara-C. Furthermore, thymidine was found to be an effective modulator of the intracellular pools of dCTP and ara-CTP in rats, bone marrow, small intestine, and colon tumor cells. The mechanism of this effect is unclear, but initial evidence indicates that specific scheduling of the sequential administration of the metabolite and the antimetabolites may be important in determining increased selectivity of antitumor effects. In vivo studies with fluorinated pyrimidines have focused on quantitating 5-fluorodeoxyuridine monophosphate (FdUMP) pools and their retention, and on the incorporation of fluorouridine (FUR) into RNA of sensitive and resistant L1210 cells. The results suggest that the retention of intracellular FdUMP pools above a threshold may be a more critical determinant in selectivity than the initial FdUMP levels achieved in target cells. Thymidine has been demonstrated to alter the pharmacokinetic parameters of 5-FU in man and in mice, but a selective modification of the antitumor activity of 5-FU has not yet been unequivocally demonstrated.

Animals↗
PubMed1980

Colony growth in soft agar of human melanoma, sarcoma, and lung carcinoma cells disaggregated by mechanical and enzymatic methods.

The effect of mechanical and enzymatic disaggregation on human malignant melanoma, soft-tissue sarcoma and lung carcinoma colony growth in soft agar was studied. The enzymatic disaggregation was advantageous in most cases of melanoma and sarcoma, giving a larger number of colonies and increasing the probability of achieving growth in soft agar. Enzymatically treated pulmonary carcinoma cell populations had lower clonogeneic potential, especially in the case of anaplastic carcinomas. Morphological studies showed that the cells growing in soft-agar colonies had the same characteristics as those of the original tumor. A linear relationship was obtained between the number of enzymatically and mechanically treated tumor cells plated and the number of colonies. Delayed plating decreased the number of colonies.

Agar↗
PubMed1980

The design of cancer chemotherapy: metabolic modulation and cellular de novo versus salvage metabolism.

Attempts were made to evaluate the degree of utilization of 'salvage' and de novo purine and pyrimidine metabolites by normal and tumor cells. The significance of unique ribonucleotide pools and their ratios were also investigated. The results indicate that while normal bone marrow cells appear to depend almost exclusively on salvage pathways for their nucleic acid synthesis, tumor cells appear to utilize both the de novo and salvage pathways. The degree of dependence of tumor cells on these pathways appears to vary considerably. Utilizing this unique difference between tumor and normal cells, attempts were made to utilize the salvage precursors with the hope of modifying selectively the effects of antimetabolites against tumor cells in vivo. Results indicate that thymidine can potentiate the in vivo toxicity of 1-beta-D-arabinofuranosylcytosine and fluorouracil. The degree of modulation by normal metabolites appears to correlate with the level of circulating salvage metabolites.

Animals↗
PubMed1980

Effects of cytosine arabinoside on unseparated bone marrow and peripheral blood cells and on specimens enriched for myeloblasts and promyelocytes.

Myeloblast and promyelocyte enriched preparations and the original unseparated specimens were compared in regard to the phosphorylation of cytosine arabinoside (ara C) and the retention of ara CTP as well as the effects of ara C on the clonogenic cells. The immature cell-enriched preparations have a significantly higher rate of ara C phosphorylation, while retention of ara CTP is not significantly different from that of the unseparated cells. No correlation was found between the measured parameters of ara C metabolism and the drug's effects on the clonogenic cells in either cell population.

Blood Cells↗
PubMed1979

Selectivity of action of 5-FU: biochemical basis.

Studies have been initiated to investigate the biochemical basis for selectivity of action of 5-fluorouracil against tumor cells. These studies included the measurement of 5-fluorodeoxyuridine monophosphate pools and the amount of 5-fluorouracil incorporated into RNA at various times following the administration of labeled 5-fluorouracil-6-3H, 5-fluorouridine-6-3H and 5-fluorodeoxyuridine-6-3H to animals bearing sensitive L1210 cells and L1210 resistant to 5-fluorouracil. The data indicate that: 1) in both cell lines the order of drug uptake into cells in vivo was in the order of fluorouride greater than fluorouracil greater then fluorodeoxyuridine; 2) there was no qualitative difference between the two cell lines in term of the extent of drug activation; 3) the data suggest a strong correlation between the amount of 5-fluorodeoxyuridine-monophosphates formed and retained at the target site and responsiveness to these agents. The effects of thymidine administered by continuous infusion and i.v. bolus injection on the antitumor activity of 5-fluorouracil was also investigated in animals bearing the induced colon carcinoma. The data suggest that thymidine, in combination with 5-fluorouracil, improves the therapeutic index of 5-fluorouracil. Initial studies on the metabolism of 5-fluorouracil in patients bearing the colon carcinoma are also reported herein.

Animals↗