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1. |
Phase Ia study of a hypoxic cell sensitizer doranidazole (PR-350) in combination with conventional radiotherapy |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 1-6
Kenji Nemoto,
Yuta Shibamoto,
Jun-ichi Ohmagari,
Yuji Baba,
Kazuyu Ebe,
Hisanori Ariga,
Yoshihiro Takai,
Atsushi Ouchi,
Keisuke Sasai,
Misao Shinozaki,
Michihiko Tsujitani,
Masakazu Sakaguchi,
Shogo Yamada,
Kiyohiko Sakamoto,
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摘要:
A phase Ia study of a 2-nitroimidazole nucleoside analog radiosensitizer doranidazole was conducted to evaluate its toxicity and pharmacokinetics in patients undergoing conventional external beam radiotherapy. Twenty-nine patients, aged 40-74 years, with a WHO performance status of 0-2 and with adequate organ functions, were entered in the study. Single administration of doranidazole was investigated first with 13 patients and then a course of five consecutive daily administrations was tested in 16 patients. Doranidazole was given i.v. 25 min before irradiation. Doranidazole doses of 400, 800, 1300 and 2000 mg/m2were evaluated in the former study, and daily doses of 800, 1300 and 2000 mg/m2were investigated in the latter study. All patients tolerated doranidazole administration. Although a transient decrease in the 24-h creatinine clearance rate was observed in five patients (one in the single administration study and four in the repeat administration study), this was not considered to be the dose-limiting toxicity. Other toxicities (hematological and gastrointestinal), which may not be related to doranidazole administration, were also mild and were not dose limiting. No neurotoxicity was observed. The average maximum concentration, area under the time-concentration curve and half-life of doranidazole in serum were 172-194 μg/ml, 502-582 μg·h/l and 4.2-4.6 h, respectively, at 2000 mg/m2. At the tested doses, administration of doranidaozle was tolerable and achieved serum concentrations at which reasonable radiosensitization could be expected. A phase Ib/II study to evaluate the feasibility and efficacy of up to 30 repeat administrations seems to be warranted.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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2. |
Interferon-α-induced pure red cell aplasia following chronic myelogenous leukemia |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 7-8
Naoto Tomita,
Shigeki Motomura,
Yoshiaki Ishigatsubo,
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摘要:
We report a case of pure red cell aplasia (PRCA) that resulted from interferon (IFN)-α therapy for chronic myelogenous leukemia. PRCA improved within 1 month after IFN-α was discontinued. This case indicates the involvement of IFN-α in the pathogenesis of PRCA.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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3. |
The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 9-19
Danièle Demarquay,
Marion Huchet,
Helène Coulomb,
Laurence Lesueur-Ginot,
Olivier Lavergne,
Philip Kasprzyk,
Christian Bailly,
Jose Camara,
Dennis Bigg,
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摘要:
BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entered clinical trials. BN 80915 is a difluoro-hCPT where the six-membered α-hydroxylactone ring of camptothecin (CPT) is replaced by a seven-membered β-hydroxylactone ring. Preclinical data reported here show that in spite of the modification to the crucial E-ring of CPTs, BN 80915 retains topoisomerase I poisoning activity as shown in living HT29 cells as well as in cell-free assays, where BN 80915 always performs better than SN-38 or TPT. In antiproliferative assays BN 80915 is also very potent as evidenced by IC50s values consistently lower than those of SN38 in sensitive cell lines as well as in their related multidrug-resistant lines overexpressing P-glycoprotein or multidrug resistance-associated protein. Furthermore, in human plasma, in contrast to CPT analogs, the hydrolysis of BN 80915 is slow, leading to improved plasma stability, and irreversible, thus avoiding toxicity related to the accumulation of active principle during excretion in the urinary tract. These findings may account for the goodin vivoefficacy observed in PC3 xenograft experiments where BN 80915 administered orally at very low doses doubled the tumor growth delay in comparison to CPT-11 administered i.p. Altogether, these results strongly support further development of BN 80915.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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4. |
Approach to a multiparametric sensor-chip-based tumor chemosensitivity assay |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 21-32
Tobias Henning,
Martin Brischwein,
Werner Baumann,
Ralf Ehret,
Ingo Freund,
Robert Kammerer,
Mirko Lehmann,
Anne Schwinde,
Bernhard Wolf,
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摘要:
Although not widely practiced by oncologists,in vitrotumor chemosensitivity assays (TCA) have proved to increase the lifetime of tumor patients in prospective clinical trials. By individualizing cancer therapy, they can support the clinician's decision which is usually based on empirically retrieved data and thereby prevent inadequate chemotherapy. We present the first results of a new sensor-chip-based technology which might be useful for a multiparametric TCA. In particular, the aspect of dynamic on-line data generation on intact cellular specimens is a major difference to alternative assays. A series of experiments has been performed on cell lines and human tumor explants. Cell cultures and tumor tissue explants were placed on miniaturized silicon and glass sensor chips. The sensor data currently analyze metabolic profiles (rates of extracellular acidification and cellular oxygen consumption) and changes in cell morphology (monitoring of electric impedance). With the cell lines, drug-associated cellular signals have been detected with all three parameters, while primary explants so far caused metabolic responses only. In particular, cellular respiration or mitochondrial activity seems to be a most sensitive indicator of acute cytotoxic effects. The experimental results were achieved using different test versions. Besides giving a status report, the theoretical potential and current problems of sensor chip technology in TCA is discussed.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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5. |
A hollow fiber model forin vitrostudies of cytotoxic compounds: activity of the cyanoguanidine CHS 828 |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 33-42
Saadia Hassan,
Manuel de la Torre,
Peter Nygren,
Mats Karlsson,
Rolf Larsson,
Elin Jonsson,
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摘要:
The hollow fiber assay is currently used as anin vivomodel for anticancer drug screening in nude mice, but it can also be used as anin vitromodel. In the current study, anin vitrohollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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6. |
Inhibition of mitotic cyclin B and cdc2 kinase activity by selenomethionine in synchronized colon cancer cells |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 43-50
Marianne Chigbrow,
Mark Nelson,
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摘要:
Selenomethionine (SeMet), an organic selenium compound, has been demonstrated to have significant chemopreventive activity. However, the mechanism of action of SeMet has yet to be identified. Previously, our laboratory found that treatment of cells with SeMet induced apoptosis and altered the cell cycle. These observations have led to further analysis of the cell cycle effects of SeMet in colon cancer cells. Synchronized HCT 116 colon cancer cells treated with 100 μM SeMet for 66 h were found to have a transient delay in G2/M phase of the cell cycle at 18 and 24 h after treatment. With this was observed an inhibition of cell growth. Coincidentally with this delay was a decrease in mitotic cyclin B RNA expression at 18 h after treatment. In addition, the cdc2 kinase activity of HCT 116 cells was decreased at 18 h. Morphological studies indicate an increase in the number of treated cells (45%) undergoing apoptosis at 66 h compared to control cells (27%). These studies demonstrate that modulation of mitotic cyclin expression and cdc2 kinase activity play a role in the ability of SeMet to inhibit tumor cell growth. A consequence of this prolonged arrest is apoptosis.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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7. |
Induction of apoptosis in human leukemia K-562 and gastric carcinoma SGC-7901 cells by salvicine, a novel anticancer compound |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 51-56
Chen Qing,
Chao Jiang,
Jin-Sheng Zhang,
Jian Ding,
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摘要:
Salvicine (a novel diterpenoid quinone compound) exhibited a marked antitumor activity on human solid tumor cell lines and BALB/c-nuhuman carcinoma xenografts in our earlier studies, and it has been chosen as a candidate anticarcinogenic compound in the preclinical research stage. The present study was undertaken in order to observe whether or not the antitumor effect of salvicine is associated with its ability to induce apoptosis. Our results show that salvicine is capable of inhibiting cell proliferation and inducing characteristic changes of apoptosis in both human leukemia K-562 and gastric carcinoma SGC-7901 cells. These effects are dose and time dependent. The results of this study strongly suggest that the antitumor effect of salvicine is associated with its ability to induce apoptosis. Meanwhile, this study also shows that the activity of salvicine against K-562 and SGC-7901 cells is similar with regards to both growth inhibition and apoptosis induction, further indicating that salvicine causes these particular effects on solid tumor cells.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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8. |
Evaluation of combretastatin A-4 prodrug in a non-Hodgkin's lymphoma xenograft model: preclinical efficacy |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 57-63
Sanaa Nabha,
Ramzi Mohammad,
Nathan Wall,
Julie Dutcher,
Bashar Salkini,
George Pettit,
Ayad Al-Katib,
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摘要:
Combretastatin A-4 prodrug (CA4P) is a new antitubulin agent currently in phase I/II clinical trials against solid tumors. We have previously reported on thein vitroactivity of CA4P against a panel of malignant human B-lymphoid cell lines. In this study, we investigated the antitumor and the antiangiogenic activity of CA4P in our diffuse large cell lymphoma WSU-DLCL2-SCID mouse model. WSU-DLCL2cells (107) were injected s.c. into 5-week-old female ICR-SCID mice. Tumor-bearing mice were treated at the CA4P maximum tolerated dose (MTD) of 800 mg/kg in different dose/schedules. CA4P showed significant antitumor activity against this lymphoma model. Best results were seen when MTD was given in two and four divided doses (400 and 200 mg/kg, respectively). CA4P given in four divided doses (4×200 mg/kg) showed a log10kill of 1.01,T/Cof 11.7% andT-Cof 12 days. Immunohistochemical staining using anti-CD31 antibody after 6, 24, 48 and 120 h treatment revealed a significant decrease in the number of tumor blood vessels after 24 h (about 80%). Only the periphery of treated tumors revealed the presence of blood vessels. Morphological examination of the tumors after tetrachrome staining showed a necrotic center in tumors of CA4P-treated animals. New blood vessel formation was noted to emerge in tumor tissues as early as 48 h following a single dose of CA4P. The G2/M arrest observedin vitrowas not detectedin vivoindicating predominance of the antiangiogenic effects with regard to antitumor efficacyin vivo. We conclude that CA4P has antiangiogenic activity in this lymphoma model and the use of this agent should be explored clinically in the treatment of non-Hodgkin's lymphoma.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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9. |
Platinum(II) and palladium(II) complexes with 2-acetylpyridine thiosemicarbazone: cytogenetic and antineoplastic effects |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 65-70
Z Iakovidou,
A Papageorgiou,
M Demertzis,
E Mioglou,
D Mourelatos,
A Kotsis,
P Nath Yadav,
D Kovala-Demertzi,
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摘要:
The effect of three novel complexes of Pt(II) and three complexes of Pd(II) with 2-acetylpyridine thiosemicarbazone (HAcTsc) on sister chromatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing antitumor and cytogenetic effects were the complexes [Pt(AcTsc)2].H2O and [Pd(AcTsc)2] while the rest, i.e. (HAcTsc), [Pt(AcTsc)Cl], [Pt(HAcTsc)2]Cl2.2H2O, [Pd(AcTsc)Cl] and [Pd(HAcTsc)2]Cl2, displayed marginal cytogenetic and antitumor effects.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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10. |
In vitro targeting of a cytotoxic analog of luteinizing hormone-releasing hormone AN-207 to ES-2 human ovarian cancer cells as demonstrated by microsatellite analyses |
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Anti-Cancer Drugs,
Volume 12,
Issue 1,
2001,
Page 71-78
Jose Arencibia,
Andrew Schally,
Gabor Halmos,
Attila Nagy,
Hippokratis Kiaris,
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摘要:
Targeting of cytotoxic agents represents a modern approach to the treatment of various cancers, that improves the efficacy and reduces peripheral toxicity. Recently we developed a powerful cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AN-207, designed to be targeted to tumors that express LHRH receptors. This analog consists of the superactive derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), linked to [D-Lys6]LHRH carrier. In the present study we investigated the cytocidal effects of AN-207 and AN-201 on the LHRH receptor-positive ES-2 ovarian cancer cells. The targeting of AN-207 to ES-2 cells in the presence of LHRH receptor-negative UCI-107 ovarian cancer cells was also evaluated by semi-quantitative polymerase chain reaction (PCR) amplification of microsatellite markers. Ligand competition assays showed a single class of high-affinity and low-capacity binding sites in ES-2 cells with a mean dissociation constant (KD) of 3.93±0.1 nM and a mean maximal binding capacity (Bmax) of 271±26.1 fmol/mg membrane protein. Kinetic assays indicated that AN-207 caused cell death in a concentration- and time-dependent manner in ES-2 cells, but not in UCI-107 cells, while the kinetics of cytotoxic effects of AN-201 were similar in both cell lines. To investigate targeting, ES-2 cells were co-cultured with UCI-107 cells, treated with 10 nM AN-207 or AN-201 for different times and then cultured for 48 h in the absence of cytotoxic agents. Genomic DNA was extracted for microsatellite analyses using different markers. Semi-quantitative analyses of the intensity of the alleles that correspond to each cell line indicated that AN-207 was selectively targeted to ES-2 cells, while AN-201 showed no selectivity for either cell line. These results extend our previous findings that AN-207 can be targeted to ovarian cancers and other tumors that express receptors for LHRH. Cytotoxic analogs of LHRH, such as AN-207, should be considered for treatment of LHRH receptor-positive tumors.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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