PubMed Health⌕ Search

Biomedical subjects

Y M Rustum

Publications and source records attributed to Y M Rustum.

At least 163 records · Page 9Linked to original sources
PubMed1985

Limitations of drug sensitivity testing in soft agar for clinical management of patients with ovarian carcinoma.

Thirty specimens from 28 patients (15 previously treated, 13 previously untreated) with ovarian carcinoma were studied in a soft agar colony-forming assay to determine whether or not the assay could be useful for treatment planning. There were sufficient colonies for drug testing in 23 cases. An in vitro drug response was found in 12 of 106 drug tests. In vivo-in vitro correlations could be made for 28 drug trials in 16 patients. Eight patients were not evaluated for response because they were clinically disease free after debulking surgery. Single agents were evaluated in vitro, although most patients received combination chemotherapy. In 23 cases the tumor was resistant in vitro and in vivo. There were two false-negative and three false-positive results. Cell aggregates that may artificially increase growth rates and apparent in vitro drug resistance were a major problem technically. In view of the problems identified, the assay in its current form should not be used routinely to direct therapy.

Aged↗
PubMed1985

Relationship between DNA ploidy, glandular differentiation, and tumor spread in human prostate cancer.

DNA ploidy was evaluated by flow cytometry for 45 human prostate carcinomas (34 prostatectomy specimens and 11 biopsies). Twenty tumors (44.4%) contained a distinct aneuploid stem line. All 11 tumors confined to the prostate gland (pathological Stage B) were diploid. The frequency of aneuploidy increased with advancing stage, and most tumors with distant metastases were aneuploid. The degree of glandular differentiation was characterized by the Gleason score. One-third of tumors with a Gleason score of 5 to 6 were aneuploid, whereas over 70% of poorly differentiated tumors with a Gleason score of 9 to 10 were aneuploid. Among diploid tumors, 45.5% were localized carcinomas (Stage B), 36.4% were characterized by invasion outside the prostate (Stage C), and 18.2% formed pelvic nodal or distant metastases (Stages D1 and D2). In nearly two-thirds of patients with aneuploid tumors, pelvic nodal or distant metastases were found. When tumors were classified according to both DNA ploidy and degree of glandular differentiation, then subgroups of tumors with the highest and lowest degree of malignant potential became apparent. Only 7.1% of diploid tumors with a Gleason score of 5 to 6 formed metastases, but 80% of aneuploid tumors with a higher Gleason score (7 to 10) formed metastases. Diploid tumors with higher Gleason scores and aneuploid tumors with lower Gleason scores had intermediate frequencies of metastases. The presence of an aneuploid stem line in prostate carcinomas indicated that the tumor had spread outside the prostate gland or had metastasized. DNA ploidy may be an important prognostic factor for human prostate cancer. DNA ploidy and the degree of glandular differentiation considered together may improve prognostic evaluation of prostate carcinomas.

DNA, Neoplasm↗
PubMed1985

Potential for selective enhancement of the in vivo metabolism of 1-beta-D-arabinofuranosylcytosine in rats by thymidine pretreatment.

In this study, the ability of deoxythymidine (dThd) to enhance selectively the metabolism of 1-beta-D-arabinofuranosylcytosine (ara-C) in rats bearing transplantable colon carcinoma was investigated. A steady-state plasma level of 375 microM dThd was achieved within 3 h after initiation of a 24-h infusion of dThd (7 g/kg/day) with a concomitant 80% reduction in circulating 2'-deoxycytidine levels. Complete recovery to control values occurred within 6 to 8 h after termination of the infusion. Under the conditions of dThd infusion, the intracellular levels of 2'-deoxycytidine 5'-triphosphate rose from 0.15 to 60 pmol/mg tumor tissue, from 2.5 to 15 pmol/mg intestinal tissue, and from 0.07 to 0.25 pmol/10(6) bone marrow cells. During the steady-state plasma concentration of dThd, the intracellular concentration of 2'-deoxycytidine 5'-triphosphate in tumor tissue was reduced by 50% at 6 h after the initiation of dThd treatment with a complete recovery 9 h thereafter. Differences in the capacity of tumor and host normal tissues to recover from the effects of dThd pretreatment were evaluated by measuring decreasing 1-beta-D-arabinofuranosylcytosine 5'-triphosphate formation with time following dThd infusion. The ability to accumulate 1-beta-D-arabinofuranosylcytosine 5'-triphosphate was reduced by 60 to 80% in normal tissues by 3 h after cessation of the dThd infusion but was decreased by only 15% in the tumor. These results suggested that delaying ara-C administration following dThd might result in less host toxicity while maintaining the antitumor effect. Sequential infusion of dThd (7 g/kg/day) for 24 h followed 3 h later by a 48-h infusion of ara-C (175 mg/kg/day), was as effective in reducing tumor mass as was dThd infusion immediately prior to ara-C and resulted in reduced host toxicity (less weight loss). The best schedule for the dThd-ara-C combination was two courses of alternating 24-h sequential infusions of dThd and ara-C with a 3-h delay in ara-C administration following dThd. These data show that under the conditions used, reductions in intracellular 2'-deoxythymidine 5'-triphosphate pools by dThd in vivo do not appear to correlate with the antitumor activity of the dThd-ara-C combination. Intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate accumulation, however, was prolonged in rat colon tumor compared to normal tissues, and selectivity of the dThd-ara-C combination in favor of the tumor could be achieved by schedule modification.

Animals↗
PubMed1984

Flow cytometric analysis of DNA aneuploidy in primary and metastatic human solid tumors.

DNA histograms were measured by flow cytometry for 656 human solid tumors (365 primary and 291 metastatic). The proportion of aneuploid cells in cell suspensions obtained by mechanical disaggregation was significantly higher than those obtained after enzymatic disaggregation (collagenase + DNAse) of the same tumor. A strong correlation was observed between the values of DNA-indices measured after staining with propidium iodide and with 4',-6-diamidino-2-phenylindole (r = 0.97). Aneuploid cells were observed in 430 tumors (66%); 30 of these had two aneuploid stemlines, and two had three aneuploid stemlines. The overall frequency of aneuploidy was 61% among primary and 71% among metastatic tumors. The median value of the DNA index was 1.67 for 224 primary aneuploid tumors and 1.68 for 206 metastatic aneuploid tumors. For most diseases, the largest proportion of aneuploid primary and metastatic tumors had DNA-indices in the hypertriploid region. No major differences in frequency and degree of aneuploidy was observed between primary and metastatic tumors. For carcinomas of the bladder and prostate, frequency of aneuploidy was higher among poorly differentiated, than among moderately and well-differentiated tumors. For carcinomas of the breast and for sarcomas, tumors with DNA-indices of greater than 2.0 were observed mostly in the poorly differentiated group. For patients with carcinomas of the bladder and prostate most tumors at earlier stages of disease were diploid; whereas most tumors at later stages of disease were aneuploid. For patients with carcinomas of the ovary, colon, and kidney, no relationship between stage of disease and aneuploidy was evident.

Aneuploidy↗
PubMed1984

Proliferative characteristics of primary and metastatic human solid tumors by DNA flow cytometry.

The percentage of cells in S-phase (S-index) was calculated from DNA histograms of 453 primary and metastatic human solid tumors (predominantly bladder, breast, colorectal, renal, prostate, ovarian and lung carcinomas, melanomas, and sarcomas). S-indices varied widely among both primary and metastatic tumors (1-48%); there was no significant difference in S-indices between primary and metastatic tumors. The S-indices for aneuploid tumors were significantly higher than for diploid tumors. When data for all aneuploid tumors were analyzed collectively, there was no significant relationship between S-index and DNA ploidy index. However, for colorectal and ovarian carcinomas S-indices increased, and for lung carcinomas S-indices decreased with elevation in the degree of DNA-ploidy. Lung carcinomas had the highest S-indices. Comparison of flow cytometry (FCM) and cytology data indicated that for most diploid tumors S-indices reflect the proportion of S-phase cells among a mixed population of normal and tumor cells. For most aneuploid tumors, the proportion of tumor cells estimated cytologically was similar to the proportion of aneuploid cells estimated by FCM. For a small proportion of aneuploid tumors a comparison of cytology and FCM data indicated the presence of a predominant diploid tumor stemline and a minor stemline with aneuploid DNA content. There was a wide spread in the values of S-indices within tumor groups defined by degree of differentiation and stage of disease at surgery.

Aneuploidy↗
PubMed1984

Serial cytogenetic analysis of a recurrent malignant melanoma.

A metastatic malignant melanoma in a 54-yr-old white female was examined cytogenetically on three different occasions. We found two different clones, one hypodiploid and another hypertriploid; however, both clones had the same markers [i.e., der(6),t(6;17), and der(17),t(1;17)]. Detailed analysis of the histopathology and clinical course suggests that these two different clones reflected different morphology and results of therapy.

Chromosome Aberrations↗
PubMed1984

Chemotherapeutic efficacy of 5-fluorouracil with concurrent thymidine infusion against transplantable colon tumors in rodents.

The therapeutic efficacy of 5-fluorouracil (FU) given concomitantly with thymidine (TdR) versus that of FU alone at an equitoxic dose was evaluated when these agents were given by 72-h continuous i.v. infusion or as an i.v. push dose through the tail vein to Fischer rats bearing a transplantable colon carcinoma or to BALB/c or C57BL/6J mice bearing murine colon tumors no. 26 or 38, respectively. In the presence of TdR, the dose of FU maximally tolerated by normal rats and mice was reduced by approximately half. In tumor-bearing rats, infusion of FU alone (150 mg/kg X 72 h) was as effective as concurrent infusion of FU (100 mg/kg X 72 h) with TdR (5 g/kg X 72 h), as evaluated in terms of tumor-free survivors (7/22 and 6/20, respectively). In addition, both regimens were more effective than an i.v. push dose of FU (200 mg/kg) or FU (80 mg/kg) and TdR (2 g/kg), which resulted in 2/18 and 0/18 tumor-free survivors, respectively. No significant differences in tumor growth inhibition were seen using either murine colon tumor, whether FU or the FU with TdR combination was administered as an i.v. push dose or as an infusion. Quantitation of the levels of TdR and thymine (T) in rat plasma obtained during infusion of various doses of TdR showed dose-dependent levels of TdR and T, indicating conversion of TdR to T in vivo. These data showed that, under the conditions employed, TdR did not modify significantly the antitumor activity of FU against rodent colon tumors. The toxicity of FU, however, could be enhanced by the coadministration of TdR, probably due, in part, to a reduced degradation of FU resulting from competition by T.

Animals↗
PubMed1984

Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer.

Twenty-six patients with metastatic colorectal adenocarcinoma were entered into a Phase I-II study of 5-fluorouracil (5-FUra)-high-dose leucovorin (CF). The starting dose of 5-FUra was 300 mg/sq m with escalation to 750 mg/sq m/week in 6 doses given by rapid i.v. injection midway during a 2-hr infusion of CF, 500 mg/sq m. Partial responses were seen in 9 of 23 patients (6 of 12 who had had previous 5-FUra). Complete normalization of liver enzymes was seen in two of these patients. Side effects were seen sporadically with 5-FUra doses up to 600 mg/sq m. At a 600-mg/sq m 5-FUra dose, 8 of 18 patients had diarrhea, and 2 of 18 had white blood cell counts less than 3000/microliter. At a 750-mg/sq m dose of 5-FUra, 6 of 11 patients had severe diarrhea and 6 of 11 had white blood cell counts less than 3000/microliter. Other toxicities were mild conjunctivitis and lacrimation, thinning of the nails, and alopecia. In bioavailability studies of CF p.o., no plasma CF could be detected. After CF i.v., mean plasma peak was 111.3 +/- 40.3 (S.D.) microM. 5-FUra-CF appears to be effective in patients clinically resistant to 5-FUra. This study is being extended to randomized trial of 5-FUra-CF versus 5-FUra alone.

Adult↗
PubMed1983

Changes in ribo- and deoxyribonucleoside triphosphate pools within the cell cycle of a synchronized mouse fibroblast cell line.

Intracellular pool levels of ribo- and deoxyribonucleoside triphosphates were monitored throughout the cell cycle of C3H10T1/2 mouse embryo fibroblast cells synchronized by isoleucine deprivation. Absolute pool sizes of ribonucleoside triphosphates were approximately 30 fold greater than those of the corresponding deoxyribonucleoside triphosphates. Of the ribonucleoside triphosphates, pool sizes of ATP exhibited the greatest change, increasing from a low of 32.7 nmol/10(7) cells during G1 to a high of 81.6 nmol/10(7) cells 2 h prior to mid S-phase. Levels of ATP subsequently declined to 40.2 nmol/10(7) cells during late S-phase, followed by a second peak of 65.8 nmol/10(7) with the onset of cell division. No significant changes in the pool sizes of UTP and GTP were found throughout the cell cycle. Of the deoxyribonucleoside triphosphates, pool sizes of pyrimidine deoxyribonucleoside triphosphates were approx. 5-10 fold greater than those of purine deoxyribonucleoside triphosphates. Low levels of deoxyribonucldoside triphosphates during G1 (0.3-1.3 pmol/10(7) cells) increased coordinately with the initiation of DNA synthesis to an initial peak during mid S-phase (0.5-6.4 pmol/10(7) cells). Declining levels of deoxyribonucleoside triphosphates during late S-phase were followed by a subsequent larger second peak (1.7-10.7 pmol/10(7) cells) during G2-M.

Animals↗
PubMed1983

Differential selectivity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in cultured human B lymphocytes and mouse L1210 leukemia.

The role of differential metabolic activation of a 5-fluorouracil (FU) prodrug, 5'-deoxy-5-fluorouridine (dFUR), in achieving selective cytotoxicity was investigated in cultured human (dFUR), in achieving selective cytotoxocity was investigated in cultured human B lymphocytes and murine leukemia L1210 cells. B cells were cross-sensitive to FU and dFUR. On the other hand, leukemia L1210 cells were sensitive to FU but resistant to dFUR. The difference in the biological activities of FU and dFUR in B and L1210 cells correlated with (a) the metabolism of dFUR to FU by intact B (60% conversion) and L1210 (no conversion) cells, and (b) the phosphorylase activity of B (660 nmoles converted in 2 hr per mg protein) and L1210 (undetectable) cells. The intracellular metabolism of FU and dFUR was studied using a reversed-phase ion-pair high pressure liquid chromatographic assay. FU and dFUR shared similar metabolic pathways in B cells; their anabolites included FU ribose and deoxyribose nucleosides and nucleotides. In L1210 cells, FU was anabolized to 5-fluorouridine triphosphate and 5-fluorodeoxyuridine monophosphate, whereas dFUR was present mainly as the unchanged drug. Further metabolism studies using dFUR with tritium label in either the FU moiety or the altered sugar moiety established that the metabolic pathway of dFUR to cytotoxic FU anabolites in the B cells was via phosphorolysis to FU. These data indicate that, on a cellular level, an FU prodrug such as dFUR, which is activated by cytosolic enzyme, has a different selectivity from that of FU, and that the basis of differential selectivity is the initial phosphorolysis to FU.

Animals↗
PubMed1983

Correlation of tumor-cell growth in four semisolid systems.

The correlation of the colony growth of cells disaggregated from human melanoma, sarcoma, lung, and ovarian carcinomas were studied in four different semisolid tissue culture assays: (a) the soft agar assay of Pluznik and Sachs; (b) the soft agar assay of Hamburger and Salmon; (c) the soft agar-methyl cellulose assay of Buick et al.; and (d) the methyl cellulose assay of Ogawa et al. There was no colony growth of tumor cells achieved in 15 of 15 cases assayed in Ogawa's methyl cellulose assay. The plating efficiency of the above mentioned tumors was similar in the assays of Pluznik and Sachs, Hamburger and Salmon, and Buick et al. However, the tumor take rate differed among these three systems. The assay of Buick et al. appears potentially useful for analysis of the biology of human tumors.

Adenocarcinoma↗
PubMed1983

Effect of 3-deazauridine on the metabolism, toxicity, and antitumor activity of azacitidine in mice bearing L1210 leukemia sensitive and resistant to cytarabine.

The effect of 3-deazauridine (DAUR) on the intracellular purine and pyrimidine nucleotide pools and on the metabolism of azacitidine (aza-CR) in L1210 cells, sensitive (L1210/0) and resistant (L1210/ara-C) to cytarabine (ara-C), was examined. The consequences of such a modulation were correlated with the therapeutic efficacy of this combination in mice bearing L1210 leukemia. In vitro and in vivo treatment of both L1210 sublines with DAUR produced a dose- and time-dependent reduction in the CTP and dCTP pools and an increase in the UTP pool. In addition to these changes in the pyrimidine nucleotide pools, DAUR produced a modest increase in the GTP pool and a marked expansion of the ATP pool in L1210/ara-C 12 hrs following in vivo drug treatment. These perturbations in nucleoside triphosphate pools were more pronounced in L1210/ara-C cells. Treatment of mice bearing L1210/ara-C with 100 mg/kg of DAUR reduced the CTP and dCTP pools in the leukemic cells by greater than 90% within 1-3 hrs after administration of the drug, with complete recovery of these pools occurring within 12 hrs. Fluctuation of the pyrimidine nucleoside pools after DAUR treatment was correlated with the subsequent increase in aza-CR metabolism and its incorporation into RNA and with the potentiation of the in vivo toxicity of aza-CR. In mice bearing L1210/0 or L1210/ara-C tumors, DAUR or aza-CR produced a less than or equal to 23% increase in life-span (ILS). Administration of aza-CR 3 hrs after DAUR, however, produced about an 80% ILS among mice bearing L1210/ara-C tumors, but no more than an approximately 20% ILS among mice bearing L1210/0 tumors. These data suggest that the therapeutic activity of the sequential combination of DAUR and aza-CR against mice bearing L1210/ara-C cannot be explained, per se, on the basis of the initial intracellular modulation of nucleotide pools, since DAUR affected these pools of the two tumors to approximately the same degree. What appears to be important, however, is that such a modulation by DAUR preferentially affected the metabolism of aza-CR in leukemic cells resistant to ara-C which are devoid of deoxycytidine kinase activity.

3-Deazauridine↗
PubMed1982

Reversed-phase ion-pair high-performance liquid chromatographic assay of 5-fluorouracil, 5'-deoxy-5-fluorouridine, their nucleosides, mono-, di-, and triphosphate nucleotides with a mixture of quaternary ammonium ions.

Several quaternary ammonium ions were evaluated in the development of a reversed-phase ion-pair high-performance liquid chromatographic assay for the separation of the known nucleosides and nucleotides of 5-fluorouracil (FU) and its analogue, 5'-deoxy-5-fluorouridine (5'-dFUR). The capacity factors of FU, 5'-dRUR, and their eight anabolites including 5-5-fluorouridjine and its mono-, di-, triphosphate and diphosphoglucose, 5-fluorodeoxyuridine and its mono;- and diphosphate nucleotides, were dependent on the chain length and concentration of the counter ions, pH, type of buffer, as well as the type of bonded stationary phase. Separation of FU, 5'-dFUR, their nucleosides and monophosphate nucleotides was readily achieved using tetrabutylammonium ion alone as the counter ion. However, under these conditions, the di- and triphosphate nucleotides were eluted from the column only after lengthy gradient elution and with poor reproducibility. Optimal conditions for a simultaneous separation of the ten fore-mentioned compounds were achieved using a two-step elution with a mixture of tetraethylammonium (C8) and tetrabutylammonium (C16) ions. The first eluent consisted of C8 and C16 ions in a mixture of acetate--phosphate buffer and methanol, the second eluent contained an additional 30 mM phosphate. FU, 5'-dFUR, their nucleosides and monophosphates and diphosphoglucose were separated by isocratic elution from a microBondapak C18 reversed-phase column using the first eluent; and the di- and triphosphate nucleotides were subsequently eluted, isocratically with the second eluent. This assay does not require gradient elution and can be completed within 50 min with good reproducibility.

Chromatography, High Pressure Liquid↗
PubMed1982

Reversible depression of the reticuloendothelial system by liposomes.

The effect of various doses of different types (reverse phase evaporation vesicles and small unilamellar vesicles) of intravenously injected liposomes on reticuloendothelial activity, as measured by the blood clearance rate of intravenously injected carbon, was investigated. Also the effect of pretreatment with reverse phase evaporation vesicles on blood clearance and tissue distribution of a second dose of similar vesicles was determined. For all concentrations used reverse phase evaporation vesicles caused a reduction in reticuloendothelial activity at least up to 4 h after injection. 24 h after administration the rate of carbon clearance returned to the control level. On the contrary small unilamellar vesicles did not block reticuloendothelial activity. Pretreatment with reverse phase evaporation vesicles (250 mumol/kg) caused an increased blood level and a decreased hepatic uptake of a second dose of the vesicles, injected 1 h after the first dose. This seems to be due to a depression of reticuloendothelial activity and not to a depletion of opsonins. Pretreatment with small unilamellar vesicles (250 mumol/kg) had no significant influence on the tissue distribution of a second dose of vesicles. Our results clearly indicate that reverse phase evaporation vesicles cause a reversible depression of reticuloendothelial activity and this depression seems to be induced by a saturation of reticuloendothelial cells with liposomes.

Animals↗
PubMed1982

Relationship between plasma Ara-C and intracellular Ara-CTP pools under conditions of continuous infusion and high-dose Ara-C treatment.

Plasma level Ara-C and Ara-U in vivo and intracellular Ara-CTP pools in vivo and in vitro were measured using high-performance liquid chromatography and radioimmunoassay. Plasma Ara-C during High Dose therapy was found in two phases; one, a peak at t1/2 of approximately 5-8 minutes, the other approaching that of Continuous Infusion with a t1/2 of about 6 to 8 hours. There appears to be no relationship between peak levels of plasma Ara-C and intracellular Ara-CTP formed during High Dose therapy. Intracellular Ara-CTP pools were found to be higher in peripheral blood than in bone marrow during High Dose treatment and were also higher in bone marrow of patients treated with High Dose rather than conventional dose Ara-C. In vitro experiments with various concentrations of Ara-C on patient cells prior to treatment suggest that patients may benefit from High Dose therapy when an increase in intracellular Ara-CTP occurred with higher extracellular concentrations of Ara-C. In patients with metabolically sensitive cells containing the necessary enzymes to activate Ara-C to Ara-CTP, where resistance is due to limited drug transport, High Dose therapy may prove beneficial. Conversely, in patients with no increase in Ara-CTP pools in vitro due to a depletion of activating enzymes, High Dose treatment may not be warranted. Therefore, it may be possible to determine patients most likely to benefit from High Dose chemotherapy by measuring pre-treatment in vitro intracellular Ara-CTP.

Arabinofuranosylcytosine Triphosphate↗
PubMed1982

Clinical pharmacological studies of concurrent infusion of 5-fluorouracil and thymidine in treatment of colorectal carcinomas.

The effects of thymidine (dThd) coadministration on the pharmacokinetics and metabolism of 5-fluorouracil (FUra) were investigated in 29 colorectal cancer patients. Five patients received 5-day i.v. infusion of FUra at 15 mg/kg/day and 24 patients received infusion of FUra (7.5 mg/kg/day, 5 days) and dThd (216 mg/kg/day, 6 days) preceded by a bolus dose of dThd (405 mg/kg). Plasma and urine concentrations of FUra, 5-fluorodeoxyuridine (FdUrd), thymine, and dThd were quantitated by a high-pressure liquid chromatographic assay. Concurrent dThd administration reduced the plasma clearance of FUra at steady state from 389.1 +/- 153.5 (S.D.) to 56.0 +/- 36.4 liters/kg/day. The mean steady-state plasma concentration of FUra in patients receiving FUra alone was 0.38 microM and was significantly lower than the 1.30 microM in patients receiving FUra-dThd. Plasma concentrations of FUra were linearly dependent on those of thymine. Furthermore, the metabolic and renal clearances of FUra decreased inversely with thymine concentrations indicating that the elimination of FUra was reduced by thymine. In contrast to the absence of FdUrd as a circulating metabolite in patients treated with FUra alone, microM concentrations of FdUrd were detected in plasma of most of the patients treated with FUra-dThd. This together with the linear correlation of FdUrd and dThd concentrations indicates that the interconversion of FUra to FdUrd was enhanced by dThd. The incidence of dose-limiting leukopenia in the FUra-dThd combination therapy was 40%. There is an inverse correlation between the plasma clearance of FUra at steady state and hematological toxicity. The plasma clearance of FUra in the toxic population was 32.0 +/- 16.8 liters/kg/day and was significantly lower than the clearance of 72.0 +/- 37.3 liters/kg/day in the nontoxic population (p less than 0.001). The corresponding critical toxic steady-state FUra plasma concentration was 1.5 microM. The biochemical effects of dThd on the incorporation of FUra and FdUrd into RNA and into acid-soluble 5-fluorodeoxyuridine monophosphate (FdUMP) in human colon tumor cells were studied in vitro. At 100 microM, dThd increased the incorporation of FUra into RNA up to 4-fold but diminished the acid-soluble FdUMP pool. Similarly, the incorporation of FdUrd into acid-soluble FdUMP was inhibited by dThd. The response rate of colorectal carcinoma to FUra was not improved by coadministration of dThd; only one of the 11 patients who had no prior FUra therapy achieved partial remission. The lack of clinical response in these patients may be partly due to the inhibition of anabolism of FUra and FdUrd to FdUMP by dThd.

Colonic Neoplasms↗
PubMed1982

A pilot study of high-dose 1-beta-D-arabinofuranosylcytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology.

1-beta-D-Arabinofuranosylcytosine (ara-C), 2 or 3 g/sq m, was administered as a 1-hr i.v. infusion every 12 hr for 10 or 12 doses to patients with acute leukemia and refractory lymphoma. Four of seven patients with relapsed or refractory acute myelocytic leukemia and two of four patients with previously untreated acute myelocytic leukemia achieved complete remission. Of five treatment failures, two patients had leukemia which was clearly resistant to high-dose ara-C, and three patients died of infections or hemorrhagic complications during periods of pancytopenia. Three patients with acute myelocytic leukemia in remission received high-dose ara-C as consolidation therapy following previous courses of intensive, multiagent consolidation chemotherapy. Two of these three patients had prolonged thrombocytopenia following high-dose ara-C. Five patients with refractory acute lymphocytic leukemia were treated. Three patients achieved partial remission, and two patients had drug-resistant disease. Complete or partial disappearance of measurable disease parameters was seen in three of three patients with refractory lymphoma. Response was seen in five of five patients with meningeal leukemia, including complete response in one patient with extensive meningeal infiltration. Toxicity of this regimen was generally moderate and limited to pancytopenia and mild nausea. Patients who had received prior multiagent consolidation chemotherapy appeared to be at greater risk for hematopoietic toxicity. Patients who had received prior cranial irradiation or intrathecal chemotherapy appeared to be at greater risk for neurological toxicity. Plasma levels of ara-C immediately after completion of the infusion were 17.96 +/- 8.02 (S.D.) and 35.0 +/- 2.8 micrograms/ml for doses of 2 and 3 g/sq m, respectively. From 160 to 720 min following completion of the infusion, the plasma levels of drug were comparable to steady-state levels achieved with a continuous infusion of ara-C at 100 mg/sq m over 24 hr. A high degree of penetration into the central nervous system was demonstrated. High-dose ara-C has substantial activity against leukemic and lymphomatous cell populations, including cell populations resistant to conventional doses of the drug, and is an effective treatment modality for patients with these diseases. The high degree of penetration into the central nervous system suggests that this drug regimen may be useful as consolidation therapy for patients at high risk for central nervous system disease.

Adolescent↗