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Biomedical subjects

S Fulda

Publications and source records attributed to S Fulda.

44 records · Page 3Linked to original sources
PubMed1997

Effect of gravity changes on the cyanobacterium Synechocystis sp. PCC 6803.

The impact of hypergravity and simulated weightlessness were studied to check whether cyanobacteria perceive changes of gravity as stress. Hypergravity generated by a low-speed centrifuge increased slightly the overall activity of dehydrogenases, but the increase was the same for 90 g and 180 g. The protein pattern did not show qualitative alterations during hypergravity treatment up to 180 g. Cells of Synechocystis PCC 6803 subjected to common stressors like salt, heat, and light clearly accumulated at least four general stress proteins (25, 31, 34, and 63 kDa, respectively). Three of these proteins could also be detected after hypergravity, but in such small amounts that their occurrence could only be taken as a weak indication of stress. Low-molecular-weight stress metabolites were not synthesized in response to hypergravity, indicating that this gravity change was unable to activate the osmotic signal transduction chain. Gravity-dependent alterations were observed only during simulated weightlessness (generated by a fast-rotating clinostat). The glutamate/glutamine ratio was significantly shifted toward a higher glutamine portion. Altogether, the results may indicate that moderate changes of gravity were hardly, if ever, sensed as stress by cyanobacteria.

Acceleration↗
PubMed1997

Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells.

The molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are only partially understood. In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. We previously identified activation of the CD95 (APO-1/Fas) receptor/CD95 ligand (CD95/CD95-L) system as a key mechanism for drug-induced apoptosis. Here, we show that therapeutic concentrations of doxorubicin, methotrexate and cytarabine also induce apoptosis via activation of the CD95 system in primary leukemia cells in vivo. CD95-resistant and doxorubicin-resistant leukemia and neuroblastoma cells display cross-resistance for induction of cell death. Down-regulation of CD95 expression was found in drug-resistant and CD95-resistant cell lines. Furthermore, up-regulation of CD95-L, previously shown to mediate drug-induced apoptosis in a variety of tumor cells, was completely blocked in doxorubicin-resistant cells. The prototype caspase (ICE/Ced-3 protease) substrate, poly(ADP-ribose)polymerase (PARP), was cleaved in sensitive, but not in resistant tumor cells following CD95 triggering or drug treatment. Since failure to activate CD95-L was not due to decreased drug uptake or increased drug efflux, non-multi-drug resistance (non-MDR) mechanisms are involved in this type of resistance. These findings suggested that an intact CD95 system plays a key role in determining sensitivity or resistance towards anticancer therapy.

Antibiotics, Antineoplastic↗
PubMed1997

Effects of WR-2721 (amifostine) and its metabolite WR-1065 on the antiproliferative activity of chemotherapeutic agents on neuroblastoma cells in vitro.

Amifostine (WR-2721) is currently being investigated as a potential protector of normal tissues during chemotherapy in adult and pediatric cancer patients. The marked reduction of bone marrow and renal toxicity by amifostine is well documented, but data are lacking whether the anticancer activity of cytostatic drugs is also preserved in neuroblastoma as the second most common pediatric malignancy. We investigated the cytotoxic effect of six drugs on two neuroblastoma cells lines chosen for their presence or absence of N-myc amplification and PGY1 overexpression: IMR-5 (N-myc 25 x, PGY1-negative), CHP-100 (N-myc 1x, PGY1-positive) in vitro in the presence and absence of WR-2721 and its active metabolite WR-1065 using the monolayer proliferation assay. Doxorubicin, vincristine, etoposide, cisplatin, 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide were equally cytotoxic with and without preincubation of WR-2721 (14 mM) or WR-1065 (40 microM) as shown by virtually identical dose-response curves and ID50 values. We conclude that WR-2721 and WR-1065 did not reduce the cytostatic activity of six commonly used drugs on neuroblastoma cell lines in vitro.

Amifostine↗
PubMed1995

Antiproliferative potential of cytostatic drugs on neuroblastoma cells in vitro.

The role of single drugs in the treatment of neuroblastoma is poorly defined. We, therefore, tested neuroblastoma cell survival after a 72 h exposure to one of 19 cytostatic drugs by monolayer proliferation assay. 6 cell lines (IMR-5, Kelly, SK-N-SH, GI-CA-N, CHP-100, CHP-134) were selected on the basis of MYCN amplification and PGY1 overexpression. ED50 drug concentrations were related to plasma levels achievable in patients during chemotherapy. More effective substances were mitoxantrone, doxorubicin, hydroxyurea, bleomycin, dactinomycin, cisplatinum, thiotepa, melphalan, carboplatinum, etoposide, vincristine, cytarabine, 6-thioguanine, cyclophosphamide, ifosfamide and zilascorb. Parental drugs (cyclophosphamide, cisplatinum) appeared more cytotoxic on a molar basis than derived drugs (ifosfamide, carboplatinum). Less effective drugs included 5-fluorouracil, 6-mercaptopurine, CCNU and procarbazine. Fractional application of a given dose was more efficient than a single dose of cyclophosphamide, ifosfamide and cisplatinum. The tested neuroblastoma cell lines showed distinct sensitivities to cytostatic drugs. Cell lines with MYCN amplification appeared more sensitive than PGY1 overexpressing cells. In conclusion, comparative in vitro testing of cytostatic drugs may provide a rationale for their clinical evaluation. Investigation of drug combinations and application of the monolayer proliferation assay to tumour biopsy material for preclinical chemosensitivity testing are clearly warranted.

Antineoplastic Agents↗
PubMed1995

[Diaries of sleep behavior].

44 young healthy students completed a sleep diary for 49 days. Gender differences were found regarding duration of sleep, time of sleep and nights with awakenings during sleep. A relationship was found between sleep quality and duration of sleep, latency to sleep onset, awakenings during sleep and degree of alertness after rising.

Adult↗
PubMedDate not supplied

Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors.

We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

Molecular determinants of apoptosis induced by cytotoxic drugs.

Recent experimental evidence suggests that apoptosis pathways such as the CD95 system are an important mediator of chemotherapy-induced apoptosis in various tumor cell lines. Therapeutic concentrations of cytotoxic drugs induce CD95 and CD95-L that mediates apoptosis via an autocrine/paracrine loop by crosslinking CD95. Interfering with CD95-L/receptor interaction by antagonistic antibodies to the receptor or by inhibition of CD95-L expression strongly reduces apoptosis. Drug-induced apoptosis critically depends on activation of caspases since apoptosis is almost completely abrogated by the caspase inhibitor zVAD-fmk. The receptor apical caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3) are cleaved resulting in processing of substrates such as the nuclear enzyme PARP. In addition, the response to cytotoxic drugs is modulated by pro- and antiapoptotic proteins of the Bcl-2 family and p53. Defects in apoptosis pathways, e.g. deficient upregulation of CD95-L, downregulation of CD95 expression or blockade of caspase activation may confer resistance to cytotoxic drug treatment. Thus, chemosensitivity of tumor cells depends on intact apoptosis pathways such as the CD95 system that are activated by chemotherapeutic drugs. These findings may have implications for drug sensitivity and resistance of tumor cells.

Antineoplastic Agents↗