摘要:

In this update, the recent developments in the treatment of patients with advanced seminoma are reviewed. Also, the approach for patients with residual disease after chemotherapy is described. It is concluded that the combination of etoposide and clsplatin seems to be the standard treatment for patients with advanced seminoma, showing a durable response in about 90% of the patients. Although the combination of etoposide and carboplatin is less effective, newer carboplatin-based combinations seem to have a comparable efficacy. Residual disease after chemotherapy can be safely observed if the diameter is less than 3 cm; however, residuals larger than 3 cm frequently show a vital tumor and surgical evaluation should therefore be considered.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Peptide nucleic acid (PNA) Is a DNA mimic with a pseudo-peptide backbone composed of amlnoethyl glycine units. Several features of PNA, such as superior hybridization affinities to RNA and DNA, high biological stability, and convenient solid-phase synthesis, make it a promising candidate for use as a gene targeting drug. Here we review the chemical and biological properties of PNA in relation to its potential as an anti-cancer drug.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The purpose of the study was to find out if saliva concentrations of methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), can predict oral mucositis in children with acute lymphoblastic leukemia (ALL) after treatment with high-dose consolidation therapy. We have also studied the relationship between the concentrations of MTX and 7-OHMTX in saliva and the unbound concentrations in plasma. Twelve patients (36 Infusions) were studied during treatment with high-dose MTX as remission consolidation therapy (5–8 g/m2by 24 h i.v. infusion followed by leucovorin rescue). Plasma and saliva concentrations of MTX and 7-OHMTX were determined concomitantly by HPLC at 20 h and at various times following Infusion. Unbound plasma concentrations of MTX and 7-OHMTX were determined after ultrafiltration. Oral toxicity was graded according to the WHO criteria (grade 0–4). The concentrations of MTX and 7-OHMTX in saliva were not directly related to the development of mucositis. In patients with oral mucositis (WHO grade 1 or greater), the ratio to 7-OHMTX and MTX In saliva at 20 h was significantly lower than In patients without symptoms (p= 0.014, Mann-Whitney rank sum test), but not at 42 and 66 h after starting the infusion. The salivary concentration of 7-OHMTX at 20 h ranged from undetectable (less than 1 nmol/l) to 1.6 μmol/l. No significant correlation was found between the unbound and total plasma concentrations of MTX and 7-OHMTX and the drug concentrations in saliva at different points in time. The concentrations of 7-OHMTX In saliva were 11, 23 and 13% of the unbound plasma concentrations at 20, 42 and 66 h, respectively, after starting the Infusion. The respective median corresponding values for MTX were 1.6, 16.1 and 61.6%. The results suggest that determinations of saliva concentrations of MTX and 7-OHMTX may predict oral mucositis. This opens up the possibility of early identification of patients at high risk of developing oral mucositis In order to intensify topical or systemic treatment of these patients.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

VX-710 or (S)-N-[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-plperidine-2-carboxyllc acid 1,7-bls(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for Its ability to reverse P-glycoprotein-mediated multidrug resistanceIn vitro. VX-710 at 0.5–5 μM restored sensitivity of a variety of multi-drug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclltaxel, Including drug-selected human myeloma and epithelial carcinoma cells, and humanMDR1cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5–2.5 μM fully restored intracellular accumulation of [14C]doxorubicin In multidrug resistant cells, suggesting that VX-710 Inhibits the drug efflux activity of P-glyco-protein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azido-prazosin with EC50values of 0.75 and 0.55 μM. Moreover, P-glycoprotein was specifically labeled by a tritiated photo-affinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50of 0.75 μM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2− to 3-fold In a concentration-dependent manner with an apparentka, of 0.1 μM. These data indicate that a direct, high-affinity Interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by theMDR1gene product In multidrug resistant tumor cells.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Overexpression of the multidrug resistanceMDR1gene product P-glycoprotein and/or the multidrug resistance-associated protein MRP confers multidrug resistance to cancer cells. The pipecolinate derivative VX-710 has previously been demonstrated to reverseMORI-mediated multidrug resistance at concentrations of 0.5–2.5 μM by direct Interaction with P-glycoprotein and inhibition of its drug efflux activity. In this study we investigated whether VX-710 as well as four other knownMDR1modulators could also reverse multidrug resistance mediated by MRP. VX-710 at 0.5–5 μM restored senstivity of MRP-expressing HL60/ADR promyelocytic leukemia cells to the cytotoxic action of doxorubicin, etoposide and vincristine. VX-710 was approximately 2-fold more effective than verapamil, MS-209 and CsA in modulating MRP-mediated multidrug resistance, whereas GF120918 had no significant effect. VX-710 was also more effective than verapamil, MS-209 and CsA In restoring the daunorubicin accumulation deficit in HL60/ADR cells and in increasing calcein uptake. A photo-affinity analog of VX-710, [3H]VF-13,159, specifically photo labeled the MRP protein and unlabeled VX-710 inhibited this binding in a concentration-dependent manner. These data suggest that VX-710 is not only a potent modulator of P-glycoprotein-mediated multidrug resistance, but also affects multidrug resistance in MRP-expressing cells and may exert its action, at least in part, by binding directly to MRP.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The anti-metastatic effect of Z-100, an immunomodulatory arabinomannan extracted fromMycobacterium tuberculosis, was Investigated in mice bearing B16 melanoma cells. Treatment of BF10 mice implanted with high metastatic B16F10 melanoma cells with a 10mg/kg dose of Z-100 resulted in the reduction of experimental pulmonary metastasis as compared with that of BF10 mice treated with saline. The number of pulmonary metastatic colonies in BF1 mice (mice implanted with low metastatic B16F1 melanoma cells) was greatly increased after the inoculation of CD4+CD11b+CD28+TCRaβ+type 2 T cells (F10-Th2 cells) derived from BF10 mice, while only a few metastatic colonies were demonstrated In lungs of BF1 mice inoculated with naive CD4+T cells. However, the numbers of metastatic colonies in BF1 mice were not increased when they were inoculated with the F10-Th2 cell fraction derived from Z-100-treated BF10 mice and the generation of F10-Th2 cells in BF10 mice was effectively suppressed by the Z-100 treatment. These results suggest that Z-100 inhibits pulmonary metastasis of B16 melanoma through the regulation of tumor-associated Th2 cells, which are a key cell in the acceleration of tumor metastasis.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The effects of glutathione (GSH) depletion by buthionine sulfoximane (BSO) or by photosensitization-induced oxidative stress using metallo-phthalocyanines (MePcS4) on etoposide (VP-16) cytotoxicity against K562 human leukemic cells were investigated. Both treatments enhanced VP-16 toxicity in a markedly synergistic way, as revealed by combination index analysis procedure. Synergistic drug Interactions were accompanied by a supra-additive induction of DNA strand breaks. The proposed role of intracellular GSH in preventing metabolic transformations of VP-16 and thus decreasing its toxicity was confirmed by electron spin resonance (ESR) monitoring of the accumulation of the VP-16 phenoxyl radical in cell cytoplasm subjected to GSH depletion. Taken together the results emphasize the beneficial effect of GSH-related oxidative stress in enhancement of etoposide toxicity and possibly in its anticancer applications.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Amifostine was developed as a radio- and chemoprotective agent. It has shown protection against whole-body irradiation, and myelo- and nephrotoxicity of cytotoxic agents both in experimental and clinical studies. Some experimental trials revealed an influence of amifostine on tumor growth or the activity of cytotoxic drugs under certain circumstances. Therefore, it was the aim of our work to evaluate the pharmacological potential of amifostine in a preclinicalin vivosituation with human xenotransplanted neuroblastomas. Human neuroblastoma cells (IMR5–75 and Kelly) were grown s.c. as xenografts In nude mice to palpable sizes (approximately 4×5 mm). Then the animals received 200 mg/kg amifostine i.p. and were treated 30 min later with one of the following cytotoxic drugs: cyclophosphamide, doxorubicin, cisplatin, Ifosfamide, vincristine and etoposide. Amifostine as the only treatment did not Influence the growth of the neuroblastomas IMR5–75 and Kelly. We observed no side effects of the compound itself. In no case did amifostine interact significantly with the antitumor effect of any cytostatic used in combination. However, amifostine mitigated the body weight loss induced by vicristine and the leukopenia induced by cyclophosphamide, cisplatin or ifosfamide, respectively. The side effects of the remaining cytostatics were—if observed at all—unchanged. We conclude that amifostine did not influence the tumor growth of xenotransplanted neuroblastomas and did not reduce the antineoplastic activity of the tested cytostatic drugs. Further investigation of amifostine as a protectant from side effects of chemotherapy In a clinical setting is warranted.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

A new formulation has been developed for the delivery of 5-fluorouracll (5-FU) in treating peritoneal carcinomatosis. The new formulation (5-FU-MS) Involves the Incorporation of 5-FU Into microspheres composed of a poly(glycolide-co-lactide) matrix. The Incorporated 5-FU is released slowly over a 3 week period. We Investigated the drug distribution and pharmacokinetics of 5-FU in rats receiving an i.p. injection of 5-FU-MS or aqueous 5-FU solution. The concentration of 5-FU was higher in the i.p. tissues (omentum and mesentery) and lower in the extraperitoneal tissues (blood plasma, lung and heart) in rats given 5-FU-MS than in rats given the aqueous 5-FU solution. Pharmacokinetic analysis showed that the area under the curve (AUC) was significantly greater In the omentum and the mesentery than In other tissues of rats given 5-FU-MS. There was no significant difference in the AUC in the tissues of rats given the aqueous 5-FU solution.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Doxorubicin- (OAW-dox, SK-OV-dox), taxol- (OAW-tax, SK-OV-tax) and cisplatin- (SK-OV-cis) resistant cells derived from the parental OAW-42 and SK-OV-3 cell lines were established. OAW-42 sublines showed high resistance, the SK-OV-3 sublines only low resistance. OAW-42 sublines showed a cross-resistance profile typical of multidrug resistance (MDR). The sublines of SK-OV-3 showed a cross-resistance profile different from the OAW-42 sublines. The mRNA expression of several resistance proteins and related factors was analyzed. An overexpression of P-glycoprotein 170 (P-170), glutathione-S-transferase-π (GST-π), thymidylate synthase (TS), glutathione peroxidase (GP) and c-junwas found In OAW-dox and OAW-tax cells. Additionally, OAW-tax cells expressed a higher mRNA level of protein kinase Cβ;2. DNA analysis revealed a 2-fold gene amplification of P-170, whereas the genes for GST-T, TS and GP were not amplified. SK-OV-dox and SK-OV-tax cells showed a decreased level of histone 3 (H3) and TS mRNA. This shows that the sublines of OAW-42 developed resistance by co-expression of several resistance-related proteins and proto-oncogenes whereas the sublines of SK-OV-3 expressed resistance by decreased expression of the proliferation-dependent proteins H3 and TS.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID