摘要:

Understanding the relationship between chemical structure and biological properties of folate analogs, particularly their Interactions with the target enzymes, transport proteins and folate-metabollzing enzyme, folylpolyglutamate synthetase (FPGS), has enabled the rational design and development of the selective thymidylate synthase (TS) inhibitors with folate-based structures for clinical uses. These compounds specifically inhibit TS devoid of concomitant effects at other loci, unlike 5-fluorouracil (5-FU). ZD1694 ('Tomudex') was designed as a non-nephrotoxic and highly active analog of N10)-propargyl-5,8-dideazafolic acid (CB3717), which Is a potent TS inhibitor but had unacceptable nephrotoxiclty caused by Its poor water solubility. The potent cytotoxic activity of ZD1694 is dependent upon active uptake into cells via the reduced folate carrier (RFC), and subsequent rapid and extensive metabolism to polyglutamate forms inside cells. Marked enhancement of the TS inhibitory activity has been noted as the glutamate chain is elongated. Polyglutamation is critical to the biological activity of ZD1694 against tumor and normal proliferating tissues. The retentive property of ZD1694 polyglutamates inside cells led to a single, infrequent administration schedule in clinical studies. ZD1694 has completed phase I and phase II evaluation with activity observed In several tumor types, particularly In colorectal cancer with a 26% objective response rate. A recent European phase III study of ZD1694, randomized against a 5-FU plus leucovorin regimen, demonstrated an equivalent response rate for advanced colorectal cancer (complete or partial responses; 20 versus 17%) and less toxicity than seen with the latter regimen. The newer selective TS inhibitors, which retain potency for TS Inhibition but are not substrates for RFC and/or FPGS, are currently under clinical evaluation. These classes of compound may have benefits for circumvention of resistance by virtue of alterations in these protein functions and for the management of toxicity.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Multidrug resistance (MDR) Is a major hindrance to the successful treatment of neoplastic disease. The development of resistance to multiple chemotherapeutic drugs Is a complex phenomenon which has been described in both tumor cell lines and human cancers. To date, two mechanisms associated with overexpresslon of membrane glycoproteins that function as energy-dependent efflux pumps to reduce Intracellular drug levels have been identified for MDR. The first described was the product of the MDR1 gene, P-glycoprotein. The second mechanism is mediated by overexpresslon of the multidrug resistance-associated protein (MRP). While these proteins both belong to the ATP-blnding cassette superfamily of transporters, they are only distantly related. Despite this low homology, they mediate resistance to a similar range of chemotherapeutic drugs. While P-glycoprotein has been well described in the literature, much less is known about the recently identified MRP. This review gives an overview of the characteristics of MRP at both the phenotypic and genotypic levels, and discusses its possible relevance in drug-refractory cancer.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Protein kinase C (PKC) is an enzyme family with serine/ threonlne kinase function which is involved in the transduction of signals for cell proliferation and differentiation. The important role played In processes relevant to neoplastic transformation, carclnogenesis and tumor cell invasion renders PKC a potentially suitable target for anticancer therapy. Bryostatin 1, a macrocyclic lactone Isolated fromBugula nerutlna, is a partial PKC agonist, and has shown potent antlneoplastic properties In vitro and invivo. Staurosporlne, an alkaloid isolated from microbial sources, is one of the most potent PKC inhibitors and has shown high antiproliferative activity Invitro, but poor selectivity. Staurosporine analogs have thus been synthesized with the aim of obtaining more selective PKC Inhibition; among these, CGP 41251 has shown reduced PKC inhibitory activity, but a higher degree of selectivity when assayed for Inhibition of different klnases. Several studies indicate a role for PKC in the regulation of the multidrug resistance (MDR) phenotype, since several PKC inhibitors are able to partially reverse MDR and inhibit P-glycoprotein (p9P) phosphorylatlon. The MDR phenotype is also associated with variation in PKC isoenzyme content, in particular with PKC-α overexpression. While adequate PKC modulation might offer an attractive concept to modulate MDR, other potential mechanisms of PKC interaction with anticancer drugs exist and have been documented, such as the enhancement of chemotherapy-induced apoptosis by saflngol, a specific PKC inhibitor. Three phase I clinical trials with bryostatin have been completed so far and have shown that myalgia is the dose-limiting toxicity, while some antitumor activity is evident. Safingol is presently undergoing a phase I clinical trial in combination with doxorubicin. While no definitive data are presently available, it appears that saflngol plasma levels approach those associated with chemopotentiatlon in animals and no pharmacokinetic interaction between the two drugs exists. Drugs targeting PKC are well worth considering for clinical trials, particularly for their potential as modulators of currently available cytotoxic agents.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

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 cytostatlc drugs is also preserved in neuroblastoma as the second most common pediatric malignancy. We investigated the cytotoxic effect of six drugs on two neuroblastoma cell lines chosen for their presence or absence of N-mycamplification and PGY1 overexpression: IMR-5 (N-myc 25x, PGY1 -negative), CHP-100 (N-myc1x, PGY1-positive)in vitroin the presence and absence of WR- 2721 and its active metabolite WR-1065 using the monolayer proliferation assay. Doxorubicin, vincristine, etoposide, cisplatin, 4-hydroperoxycyclophosphamlde and 4- hydroperoxyifosfamide were equally cytotoxic with and without preincubation of WR-2721 (14 mM) or WR-1065 (40µM) as shown by virtually identical dose-response curves and ID50values. We conclude that WR-2721 and WR-1065 did not reduce the cytostatic activity of six commonly used drugs on neuroblastoma cell linesin vitro.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The plasma pharmacokinetics of a second generation anthracycline derivative, Idarubicin (Ida), have been studied in 17 patients with acute myelocytic leukemia (AML) and high risk features. The drug (10mg/m2) was given in a randomized cross-over design as 3 min and 2 h Infusions for three consecutive days. Cytosine arablnoside (Ara-C, 1 g/m2) was given on days 1-4. The plasma concentration time course of Ida was most properly described by the three-compartment pharmacokinetic model, independent of administration time. The maximum plasma concentration (Cmax) of Ida was reduced by a factor of 3 by Increasing the Infusion time from 3 min to 2h. The pharmacokinetic pattern of the active metabolite idarubiclnol (IdaOH) was only to a minor extent affected by the longer Infusion time. The time course of IdaOH following each dose of Ida was accurately described by the one-compartment model with a first-order formation phase. The area under the plasma concentration versus time curves (AUC) of Ida and IdaOH were not affected by the administration time. Following Ida in combination with Ara-C, the median duration of leukopenia (<1.0 X 1 02;/I ) was 14 days (range 5-56) and of thrombocytopenia (<50x103/l) was 22 days (range 7- 120). The large majority of patients developed infectious complications. Two patients with MDS-AML showed a good response. The results of the present study give no evidence of reduced hematologlc toxlcity by increasing the administration time of Ida from 3 min to 2 h. However, minimizing Cmax, by administration of Ida as prolonged infusion during a 3 day course, might be clinically important in order to reduce cardiotoxicity and hopefully to increase anti-tumor efficacy through an Increased accumulation of Ida and IdaOH In leukemic cells.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Taxol cytotoxicity was evaluated in human head and neck squamous carcinoma cell lines growing as multicellular tumor spheroids (MTS) and compared with monolayered culture using conventional clonogenic assays. End points were respectively the concentration inhibiting 50% of the cellular growth (IC50) in clonogenic assays and the concentration required to induce a 50% decrease in the MTS volume (ID50) or number in the overall spheroid population (SCC50). A significant difference was observed when the cells were exposed for 10 days to Taxol as a consequence of the different growth kinetics of the spheroids. After 16 day exposure of spheroids to Taxol, no difference remained between ID50and IC50. In addition, a significant correlation was found between individual spheroid sensitivity to Taxol (ID50) and the spheroid population sensitivity (SCC50). Both parameters (ID50and SCC50) defined in cell models appear useful for the evaluation of chemosensitivity of threedimensional structures known to be closer toin vivotumor models.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We previously reported that 5-aza-2’-deoxycytldlne (5-Aza- CdR) In combination with a\\-transretinoic acid (ATRA) produced a synergistic antineoplastic effect on DLD-1 colon carcinoma cells. We also observed that 5-Aza-CdR, a potent inhibitor of DNA methylation, increased the expression of retinoic acid receptor (RAR)-β). Methylation of cytosine in the promoter-first exon region of genes has been reported to silence their expression. In an attempt to clarify the mechanism responsible for the activation of the RAR-βgene by 5-Aza-CdR in DLD-1 colon carcinoma cells, we investigated its methylation state by Southern blotting. Our results indicate that DNA hypermethylation of the RARβgene, a putative tumor suppressor gene, may be the mechanism of silencing its expression in these tumor cells. We also reported that a different schedule of 5-Aza-CdR and ATRA produced a synergistic antineoplastic effect on the colon carcinoma cells.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Epidemiological studies have demonstrated a correlation between regular aspirin (acetylsalicylic acid; ASA) use and a decreased risk for the development of cancer. We here show that ASA inhibits the growth of 12V-ras-transformed rat fibroblasts In vitro at pharmacological concentrations. This effect appeared to be unrelated to inhibition of cyclooxygenase, since other cyclooxygenase inhibitors did not Inhibit cell growth. A number of nuclear transcription factors have been implicated as mediators of transformation. ASA has recently been reported to inhibit the activation of one such factor, NF-kB. We found that NF-kB binding activity was decreased in ASA-treated 12V-ras-transformed cells. Inhibition of NF-kB activation was not due to a general inhibitory effect, since AP-1 binding activity was not affected. We conclude that ASA inhibits the growth of 12V-ras-transformed fibroblasts, possibly via inhibition of NF-KB.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Two major steps in our study on the treatment of skin tumors by photochemotherapy (PCT) were the development of a skin tumor model In hairless mice by chemical carcinogenesls and by the use fluorescence spectroscopy, a semi-quantitative and non-invasive method, to determine the time after l.p. in|ectlon of photosensltizer when the tumor/normal skin ratio is the highest. Carcinogenesis provided mice bearing many benign papillomas and these were used to determine the tumor/normal skin ratios of two photosensltlzers by fluorescence spectroscopy. Hematoporphyrin derivative (HpD) (5 mg/kg body weight) and mtetra( hydroxyphenyl)-chlorln (m-THPC) (0.3 mg/kg body weight) were injected, and fluorescence measured at 4, 8, 24, 48, 72 and 96 h after Injection. The best tumor/normal skin ratio was 6.2 for HpD and 5.1 form-THPC. The times required to reach these ratios were 48 h for HpD and 72 h form-THPC. Published reports Indicate thatm-THPC gives a much higher tumor/normal skin ratio than HpD. These results must be confirmed by organic extraction. Photodynamic therapy with the same doses of HpD andm-THPC used In this pharmacoklnetic study must also be carried out to compare the toxicities of the two photosensitizers and to determine which is best for this type of tumor.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The alkylating agentm-/V,/V-bis(2-chloroethyl)aminocinnamic acid (m-ACA) and four new homo-aza-steroidal esters were studied for their ability to induce chromosomal abnormalities and to affect protein synthesis In human lymphocytesIn vitro. A mltotic Index reduction and an increase in the total number of aberrations were observed. Analysis of chromosomal abnormalities has shown that these are mainly chromatid breaks. A decrease in protein synthesis was also observed that seems to fit with the order of activity of the above compounds reflected in the induction of chromosomal aberrations. The observation that protein synthesis and the induction of chromosomal aberrations are affected by these chemicals may reflect interactions between these molecules and DNA that result In structural chromosome changes and decreased protein synthesis.

ISSN:0959-4973    

出版商:OVID    

年代:1997

数据来源: OVID