摘要:

The growth of solid tumors to a clinically relevant size is dependent upon an adequate blood supply.1This is achieved by the process of tumor stroma generation where the formation of new capillaries is a central event.1,2Progressive recruitment of blood vessels to the tumor site and reciprocal support of tumor expansion by the resulting neovasculature are thought to result in a self-perpetuating loop helping to drive the growth of solid tumors.3The development of new vasculature also allows an ‘evacuation route’ for metastatically-competent tumor cells, enabling them to depart from the primary site and colonize initially unaffected organs.4Several molecular and cellular mechanisms have been identified by which tumor parenchyma may exert its angiogenic effect on host endothelial cells.1–3,5–7As a result of this paracrine influence, tumor-associated endothelial cells acquire an ‘immature’ phenotype1manifested by rapid proliferation, migration, release of proteases and expression of cytokines, endothellal-specific tyrosine kinases (e.g.flk-1, tekand others) as well as numerous other molecular alterations.3Consequently a network of structurally and functionally aberrant blood vessels is formed within the tumor mass.8There is also evidence that endothelial cells themselves, and likewise other stromal cells, may act reciprocally to alter the behavior of adjacent tumor cells in a paracrine or cell contact mediated fashion.3For example, production of interleukin 6(IL-6) by endothelial cells may have a differential effect on human melanoma cells expressing different degrees of aggressiveness.9In this manner endothelial derived cytokines could conceivably contribute to tumor progression by suppressing the growth of the less aggressive tumor cells and promoting dominance of their malignant counterparts in ‘strategic’ perlvascular zones. Distinct biological features expressed by tumor-associated vasculature may serve as potential prognostic markers of disease progression as well as novel targets for therapeutic intervention.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Glucocorticosteroids (GC) play an important role in the treatment of neuro-oncologic patients. GC are used for the management of malignant brain tumors, either primary of secondary, neoplastlc epidural spinal cord compression (NESC), as adjuvant chemotherapy of some central nervous system tumors and perioperatively in brain surgery. GC are believed to exert their influence on brain tumors mainly by reducing the tumor-associated vasogenic edema, probably by decreasing the increased capillary permeability of the blood-brain barrier (BBB). Experimental as well as clinical studies applying computed tomography, magnetic resonance and PET have supported these theories. However, other mechanisms have been proposed and investigated, such as a reduction of cerebral blood flow and oncolytic effects, the latter being controversial. The effect of GC is best observed in patients with cerebral metastases and gllomas. Studies on the effect of non-steroidal anti-inflammatory drugs (NSAIDs) gave confiding results. Although some prefer methylprednisolone, dexamethasone is the GC given in the majority of neuro-oncologic patients, at an empirically chosen dosage of 4 mg qid. Dose-effect studies in patients with cerebral metastases as well as in patients suffering from NESC have been performed and lower doses in a twice dally regime may be sufficient. Side-effects may be divided in three groups: those originating from the mineralocorticold activity, the withdrawal of the drug and the chronic excess GC administration. Steroid myopathy is the most frequent occurring serious side-effect in neuro-oncologic patients. Others include gastrointestinal perforation and hemorrhage, opportunistic infections, steroid diabetes, and skin and facial changes. The most important interaction is that with phenytoin. The influence of dexamethasone on the effects of chemotherapy and radiotherapy is also discussed. New developments in GC treatment include the local administration of dexamethasone.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

BW502U83, an arylmethylaminopropanediol (AMAP), showed to be partially cross-resistant in a P-glycoprotein-positive and in a P-glycoprotein-negative, doxorubicin-resistant cell line, while no cross-resistance was noticed in a cisplatin-resistant cell line. Interstrand cross-links were not observed, but BW502U83 induced extensive DNA strand breaks. In a feasibility study the effect of intra-arterially BW502U83 was tested. One patient with a hepatocellular carcinoma showed partial remission and signs of a tumorlysis syndrome, another patient with a hepatocellular carcinoma improved clinically. A patient with soft tissue sarcoma had stable disease. Transient increase in SGOT, SGPT and LDH were observed, but no systemic side effects.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Metastatic spread of tumors to the meninges is a frequent complication of many malignancies and is difficult to treat. We describe the case of a patient who developed carcinomatous Involvement of the meninges from a breast adenocarcinoma. Despite intrathecal treatment with conventional and experimental agents, the patient's cerebrospinal fluid (CSF) was not cleared of malignant cells until thiotepa and cytarabine were given in combination. This clinical observation led us to assess thein vitroactivity of the combination of thiotepa and cytarabine in clonogenic cell survival assays. The human breast adenocarcinoma cell line MCF-7WTand its doxorubicin-resistant variant MCF-7ADRwere exposed to thiotepa and cytarabine either singly or in combination. We have found that the combination of the two drugs resulted in more than additive cytotoxicity than would have been predicted from the cytotoxicty of either drug given alone. We discuss the implications of these findings on the clinical management of patients with carcinomatous spread to the meninges.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A monoclonal antibody (A7) was produced which recognizes an oncofetal antigen expressed on glloblastoma multiforme cells, fetal brain, fetal kidney, but not adult tissues. Radioimmunoprecipitates of Zwittergent 3–14 solubilized glioblastoma cells identified a single band at 138 kDa on 8% polyacrylamide sodium dodecylsulfate gels. Distribution studies of A7 in mice demonstrated a tri-phasic serum clearance oft1/2α= 2.1 h,t1/2β= 16.7 h andt1/2γ= 151.1 h. Tumor localization studies using the U-87 MG xenograft demonstrated the ability of A7 to localize with a tumor: blood ratio of 1.294 ± 0.094 as compared with 0.293 ± 0.051 for control antibody AC. A7 does not damage cell membranes and is not internalized when bound to reactive tumor cells.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

KW-2149 is a new, semisynthetic, C-7-N-substituted, mitomycin C (MMC) analog showing equal or superior anti-tumor activity in bothin vitroandin vivoassays The preclinical activity profile combined with the hematological toxicity data in rodents and the water solubility of the compound compare favorably with MMC. The aim of this phase I study was to determine the toxicity profile and the optimal dosage of KW-2149. In this phase I study 37 patients received 97 courses of KW-2149 administered as an i.v. bolus injection every 21 days at sequential dose levels: 5, 10, 17, 25, 35, 47, 60, 75, 90 and 100 mg/m2. Hematologlcal toxicity was moderate even at the 100 mg/m2dose level. Grade IV leucopenia and thrombocytopenia were observed in one of three patients at the 100 mg/m2dose level. There was some evidence of a delayed-type bone marrow toxicity. Pulmonary toxicity was dose limiting, with grade III toxicity occuring in all three patients treated at a dose of 100 mg/m2. The type of lung toxicity was similar to the one observed with other anti-tumor antibiotics. No renal or cardiac toxicity was observed. Other toxiclties were generally mild. Antitumor activity was observed in four patients. Data of drug monitoring demonstrated rapid metabolism and/or distribution of KW-2149 with a short half-life and the emergence of the cytotoxic metabolites M-16 and M-18. The dose-limiting toxicity of KW-2149 is pulmonary toxicity.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The selection of the starting dose for initial clinical trials of anticancer agents is mostly determined by toxicological endpoints in mice (LD10). So far, very few attempts have been made to evaluate the potential value of cytotoxicity assays for this purpose. The present study was undertaken as a first attempt to Investigate the relationship between cytotoxicity of anticancer drugsin vitroand pharmacokinetic parametersin vivoin patients, at suggested maximum tolerated doses. Using the fluorometric microculture cytotoxicity assay (FMCA), we determined the concentration giving 50% cell survival (IC50)in vitro, for 25 cytotoxic drugs in fresh preparations of normal peripheral blood mononuclear cells (PBMC) and of tumor cells from patients with acute or chronic lymphocytic leukemia (ALL or CLL). Using linear regression, we investigated the relationship between the IC50s and clinically achievable peak plasma concentrations (Cmax) or concentration-time products (C × T) in humans. The clinical data was obtained from the literature. Based on all drugs tested, good correlations were obtained between IC50s for CLL cells, and both Cmaxand C × T (R≈ 0.7, p < 0.0002), and for ALL cells and normal PBMC between IC50and Cmax, while the two latter cell types showed somewhat weaker relationships to C × T. Using the IC50data of CLL cells, predictions of Cmaxand C × T exceeded 1 log for only four drugs. No tendencies to under- or overprediction within different classes of drugs were noted. The results demonstrate a significant relationship between toxicityin vitroand achievable systemic exposure of anticancer drugs in humans, which suggests that non-clonogenicin vitroassays for drug sensitivity testing may provide pharmacokinetic information useful in the development of investigational cytotoxic drugs.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The protein kinase C inhibitor, staurosporine derivative CGP 41 251, was more efficient than staurosporine in the reversal of decreased anthracycline uptake in the anthracycline-resistant cell subline (A2780/ADR) of ovarian carcinoma. Staurosporine was more efficient than CGP 41 251 in the induction of cytometrically determined DNA fragmentation (cytofluorometric equivalent of apoptosis) in A2780 parental human ovarian carcino-ma cells compared with the drug-resistant A2780/ADR subline and in both human leukemia K-562 cells as well as mouse leukemia L1210 compared with the araC-resistant L1210 cells. Staurosporine was a more potent inhibitor than CGP 41 251 of DNA synthesis in both araC-sensitive and -resistant mouse leukemia L1210 cells. CGP 41 251 was a slightly more efficient inhibitor of thymidlne incorporation than staurosporine in human leukemia K-562 cells and its combination with araC had a higher inhibitory effect on the DNA synthesis in this cell line than staurosporine. CGP 41 251 exerted DNA synthesis inhibitory effects on both araC-sensitive and -resistant L1210 cells. Staurosporine-induced DNA synthesis inhibition in both araC-resistant and -sensitive L1210 mouse leukemia cells was decreased after combined administration with araC.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Mesothelioma is a malignant tumor of the serous surfaces in the thorax and abdomen, which has proved exceptionally resistant to treatment. A recent phase II trial of a high-dose methotrexate regime on 63 Norwegian patients has, however, achieved a response rate of 37%. Some responses have also been achieved using interferon (IFN)-γ administered intrapleurally or recombinant (r) IFN-α administered subcutaneously. Our earlierin vitrosensitivity studies of mesothelioma cell lines showed that IFN augments the response to chemotherapeutic agents in mesothelioma. The aim of this study was to assess the response of four mesothelioma cell lines, derived from diffuse asbestos-related pleural malignant mesothelioma, to methotrexate alone and in combination with recombinant IFN-α and IFN-γ. Anti-proliferative effects were assayed by vital dye exclusion. A combination of IFN-α and IFN-γ consistently augmented the response of the cell lines to methotrexate, by as much as 75% for one cell line, although the response to the individual IFNs was variable. We were also able to compare the effects of natural IFN-β with those of IFN-α and IFN-γ. The IFN-β sensitivity profile for each of the four cell lines was similar to that of IFN-α. In two cell lines, the combination of IFN-β and IFN-γ produced a similar effect to the IFN-α and IFN-γ combination.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT; NSC 94600) and its derivatives. This drug has been reported to display effective antitumor effects on a variety of human tumor models xenografted in nude mice. However clinical studies of sodium CPT have revealed that the open-ring form of the drug is a poor inhibitor of topo I and much less potent antitumor agent than CPT lactone. However, the insolubility of CPT lactone makes it difficult to devise a suitable formulation for further clinical testing. In view of these observations, we report here the successful incorporation of CPT into a liposome-based drug delivery system (LCPT) composed of DPPC:Sph:CHOL:PI (2.4:6.6:1.0:0.05 M ratio) that can be used as a suitable formulation for clinical testing of the drug. Higher incorporation efficiency was observed when the total phospholipids: drug ratio = 40 and the cholesterol content = 1%. Image analysis of the CPT-containing liposomes with freeze-fracture electron microscopy has indicated that CPT significantly increased the interlamellar space of the vesicles as a result of its intercalation between lipid bilayers. This has occurred with no major disruptive effects on the bilayer structure. Thein vitrodrug release study in human serum was characterized by an initial rapid loss of 50% of contents during 4 h, followed by a slow leakage of the remaining 50% of the total drug over a 20 h period. When tested for its antitumor activity on nude mice xenografted with human malignant melanoma and breast carcinoma, LCPT displayed effective antitumor activity with minimal host toxicity. For example, single i.m. injection of LCPT at 10 mg/kg has produced complete tumor regression to nude mice xenografted with CLO beast carcinoma. Likewise, similar results were obtained with the nude mice xenografted with human malignant BRO cells melanoma. These results appear to suggest that i.m. administration of liposome-incorporated CPT has considerable potential for the treatment of human neoplastic diseases, especially lymph node metastases.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID