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(1/2270) Electronic volume analysis of L1210 chemotherapy.

The rapid analysis of in vivo chemotherapy on the L1210 ascites tumor grown in C57BL/6 X DBA/2F1 mice has been shown by means of an electronic volume analysis. The drugs were injected on the 4th day of tumor growth, and the cells in the peritoneal cavity were studied at 24-hr intervals on the 5th through 7th day. Using the electronic cell volume distributions, combined with labeling indices, cell morphology, and cell counts, it was found that the alkylating agents. 1,3-bis(2-chloroethyl)-1-nitrosourea and cyclophosphamide, at the dosages used, were more effective than the S-phase-specific drugs, palmitoyl ester of 1-beta-D-arabinofuranosylcytosine, vincristine, and methotrexate.  (+info)

(2/2270) The incorporation of 5-iodo-2'-deoxyuridine into the DNA of HeLa cells and the induction of alkaline phosphatase activity.

Inhibition of DNA synthesis during the period of exposure of HeLa cells to 5-iodo-2'-deoxyuridine (IUdR) inhibited the induction of alkaline phosphatase activity. This finding, taken together with previous findings that IUdR did not induce alkaline phosphatase activity in the presence of 2-fold molar excess thymidinemonstrated that IUdR incorporation into DNA is correlated with the increase in alkaline phosphatase activity. With the exception of an interim period described in the text, induction of alkaline phosphatase activity was linearly related to medium concentrations of IUdR of up to at least 3 muM. However, the extent of IUdR substitution in DNA did not appear to be related to the degree of enzyme induction. Alkaline phosphatase activity continued to increase at medium concentrations of IUdR from 1 to 3 muM, while little further substitution of DNA occurred.  (+info)

(3/2270) Difference between mammary epithelial cells from mature virgin and primiparous mice.

Mammary epithelial cells from mature virgin mice are similar to those from primiparous mice in several respects. However, there is one known difference. The cells from the mature virgin must traverse the cell cycle in order to become competent to make casein and enzymatically active alpha-lactalbumin in vitro; those from the primiparous animal can make these proteins without first traversing the cycle. In this regard, cells from human placental lactogen- and prolactin-treated mature virgins are, after involution, similar to those from primiparous mice. The developemental block in the cells from the mature virgin, imposed by preventing cell cycle traversal, has been partially delineated. It does not appear to reside at the levels of ultrastructural maturation or the formation of casein messenger RNA. Rather, the lesion is postranscriptional and may be at the level of translation, or posttranslational modification, or both.  (+info)

(4/2270) Differential expression and phosphorylation of CTCF, a c-myc transcriptional regulator, during differentiation of human myeloid cells.

CTCF is a transcriptional repressor of the c-myc gene. Although CTCF has been characterized in some detail, there is very little information about the regulation of CTCF activity. Therefore we investigated CTCF expression and phosphorylation during induced differentiation of human myeloid leukemia cells. We found that: (i) both CTCF mRNA and protein are down-regulated during terminal differentiation in most cell lines tested; (ii) CTCF down-regulation is retarded and less pronounced than that of c-myc; (iii) CTCF protein is differentially phosphorylated and the phosphorylation profiles depend on the differentiation pathway. We concluded that CTCF expression and activity is controlled at transcriptional and post-transcriptional levels.  (+info)

(5/2270) Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site.  (+info)

(6/2270) Metabolism of the new liposomal anticancer drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine in mice.

Metabolism and excretion of the new antitumor drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) was investigated in mice. Mice were injected i.v. with tritium-labeled liposomal NOAC (4 micromol/mouse). Analysis of HPLC-purified extracts of liver homogenates by liquid chromatography coupled with mass spectrometry revealed only the presence of unmetabolized drug. To study the excretion of the administered drug, mice were injected with tritium-labeled liposomal NOAC or as comparison with 1-beta-D-arabinofuranosylcytosine (ara-C; 4 micromol/mouse) and housed up to 48 h in metabolic cages. Urine and feces were collected at different time points and the kinetics of excreted radioactivity were determined. After 48 h, 39% of the injected [5-3H]NOAC radioactivity was excreted in urine and 16% in feces, whereas ara-C radioactivity was only found in urine with 48% of the injected dose. Feces extracts and urine were purified by HPLC and radioactive fractions were further analyzed by liquid chromatography coupled with mass spectrometry. The radioactivity of feces extracts of NOAC-treated mice was composed of unmetabolized NOAC, hydroxylated NOAC (NOAC + OH), its sulfated derivative (NOAC + OSO3H), and unidentified metabolites, whereas in urine, the hydrophilic molecules ara-C and ara-U were found. During the period of 48 h only 2% of the injected NOAC was eliminated in its unmetabolized form, whereas 25% was identified as main metabolite ara-C. Urine collected during 48 h in ara-C-treated mice contained 33% of the injected dose as unmetabolized drug and 13% as the main metabolite ara-U. Thus, NOAC is metabolized by two major pathways, one leading to the hydrophilic metabolites ara-C and ara-U and the other to hydroxylated and sulfated NOAC.  (+info)

(7/2270) ESHAP as salvage therapy for refractory non-Hodgkin's lymphoma: Taiwan experience.

BACKGROUND: The ESHAP regimen, a combination of the chemotherapeutic drugs etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin, has been shown to be active against refractory non-Hodgkin's lymphoma in therapeutic trials. We were interested in determining whether this regimen would be effective and tolerable for Chinese patients. METHODS: Thirty-two patients with refractory/relapsed non-Hodgkins lymphoma (23 intermediate-grade and nine high-grade) were enrolled in this study. Etoposide was administered at a dose of 40 mg/m2/day as a 1 h intravenous infusion from day 1 to day 4, solumedrol 500 mg/day was given as a 15 min intravenous infusion from day 1 to day 5, ara-C 2 g/m2 was given as a 2 h intravenous infusion on day 5 and cisplatin was given at a dose of 25 mg/m2/day as a continuous infusion from day 1 to day 4. Clinical efficacy and toxicity were assessed on the basis of the WHO criteria. RESULTS: Ten patients (31.3%, 95% Cl 15.2-47.4%) attained complete remission (CR) and seven had partial remission (PR). The overall response rate was 53.1% (95% Cl 35.8-70.4%). In eight of the 10 CR patients, the remission lasted for more than 8 months. The remaining two patients had CR of 5 and 6 months. The median duration of CR was 12.2 months (range 5-22 months). Myelosuppression with subsequent infections was the major toxicity. Severe leukopenia (WBC < 1000/microliter) lasted for an average of 12 days and thrombocytopenia (< 25,000/microliter) 18 days. One patient (3.1%) died of neutropenia-associated sepsis within 4 weeks after treatment. Non-myeloid toxicities included alopecia in 66% (28% grade 2, 22% grade 3), stomatitis in 72% (25% grade 2, 28% grade 3, 13% grade 4), hepatotoxicity in 9% (3% grade 2), renal toxicity in 13% (6% grade 2, 3% grade 3) and infection in 56% (18% grade 2, 25% grade 3, 13% grade 4). The majority of the responders relapsed within 2 years after ESHAP treatment. Median survival for all patients was 8.6 months. CONCLUSIONS: ESHAP is an active and tolerable regimen in Chinese patients with relapsed/refractory lymphoma, but the duration of remission is brief and without significant impact on survival.  (+info)

(8/2270) Developing hypothalamic dopaminergic neurones as potential targets for environmental estrogens.

Environmental chemicals which mimic the actions of estrogen have the potential to affect any estrogen responsive tissue. The aim of the present study was to investigate their potential to mimic the effects of 17beta-estradiol (E2) on developing primary rat hypothalamic dopaminergic (DA) neurones maintained in a chemically defined medium. We now show that both E2 and octylphenol (OP), but not the non-aromatizable androgen, dihydrotestosterone, enhanced the uptake of [3H]DA by the cultured cells, whereas they had no effect on the uptake of [14C]GABA. Although the sensitivity of responses may change with the age of the developing cultures, the dose response curves for E2 and OP were typically 'bell-shaped', with a rise in response followed by a decline to control levels with increasing concentrations. Effects were seen as low as 10(-14) M for E2 and 10(-11) M for OP. Responses to E2 (10(-12) M) and OP (10(-9) M) were reversed in the presence of the antiestrogen, ZM 182780 (10(-5) M). This study thus provides direct evidence, using a mechanistic rather than toxicological end-point, in support of the hypothesis that inappropriate exposure to environmental estrogens at critically sensitive stages of development, could potentially perturb the organisational activities of estrogen on selected neuronal populations in the CNS.  (+info)