摘要:

This retrospective study was designed to evaluate possible relationships between the number and types of concomitant medications administered to patients on the first day of therapy in phase I trials and demographic characteristics, outcome measures and toxicities. Concomitant medications received by 690 patients enrolled on 28 phase I trials between August 1985 and January 1996 were grouped into 31 categories based on the American Hospital Formulary Service 1993. These patients received 1650 cycles of treatment with investigational agents (median 2 cycles per patient). Median duration on-study was 49 days (range 1–776 days). Clinical response rate (complete, partial, minor) was 3.8% Only three toxic deaths occurred (0.4%). Nearly and patients (90.9%) received at least one concomitant medication on the first day of therapy. The number of concomitant medications directly correlated with poor performance status (rsp=0.27, p<0.0001) and indirectly with duration on-study (rsp=-0.18, p<0.0001). The dose of the investigational agent administered during the first course of therapy was not related to concomitant medications on the first day of therapy. Most importantly, no relationships were observed between concomitant medications and either toxicities or clinical response to therapy. We conclude that patients who are receiving concomitant medications should not systematically be excluded from phase I studies, [r 1999 Lippincott Williams & Willkins.]

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The clinical pharmacokinetics of the antineoplastic agent Irinotecan (CPT-11) are associated with substantial Inter-patient variability. The degree to which this variability In CPT-11 exposure Impacts upon the response and toxicity of the drug has not yet been properly determined. In general, the area under the plasma concentration-time curve (AUC) is an appropriate indicator of exposure, but requires collection of up to 17 timed blood samples. This presents difficulties if large-scale population samplings are required. The present study involved the development and validation of a strategy to estimate the AUCs of thelactone and total (i.e. lactonepluscarboxylate) forms of CPT-11 and its active metabolite SN-38 from a limited number of blood samples in patients co-treated with cisplatin. Using data from 24 patients, univariate and multivariate regression analyses were employed to generate the models. The best predictive models for simultaneous estimation of CPT-11 and SN-38 AUCs were obtained with three time points at 0.5,1.67 and 5.50 h after start of the 90 min l.v. infusion of CPT-11. The models were tested separately in another group of 24 patients receiving the same combination treatment. This validation set demonstrated that CPT-11 and SN-38 AUCs after standard does administration could be predicted sufficiently unbiased and precisely with three timed samples to warrant clinical application.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Intoplicine, an antitumor drug which interacts with both topoisomerase enzymes I and II, has demonstrated a broad spectrum of activity in preclinical studies. This indicates further clinical evaluation. In the present phase I study, with the primary objective to determine the maximum tolerated dose, intoplicine was administered by a 24 h continuous infusion every 21 days to 32 patients with solid malignant tumors. The patients received 12–540 mg/m2by a central venous catheter. Liver toxicity was dose limiting. One patient died in a hepatic coma after the first course (dose 640 mg/ m2), which was associated with intoplicine treatment. Other side effects were sporadic and mild. Myelotoxicity was virtually absent. Twenty-two patients had stable disease for four to six courses of treatment. The plasma concentration-time curves were compatible with standard linear pharmacokinetic models, with a protracted terminal half-life (mean 115 h). Although one sudden death occurred probably due to intoplicine toxicity, we nevertheless feel that research with intoplicine should continue, mainly because of its preclinical activity and Its unique mechanism of action. The recommended dose for phase II studies with intoplicine administered as a 24 h infusion is 384 mg/m2. Liver toxicity, also seen in studies employing other dosages and Infusion durations, should be investigated extensively in further clinical studies.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

A prospective evaluation of high-dose ifosfamide (IFO)-related nephrotoxicity in adults and young adults previously treated with cisplatin, methotrexate (MTX) and standard-dose IFO was performed. Eighteen patients (median age 22) with recurrent osteosarcoma were studied: 11 were pretreated with MTX, cisplatin and standard-dose IFO, and seven with MTX and cisplatin. The treatment was comprised of four cycles of high-dose IFO (15 g/m2over 5 days Cl) and mesna at equivalent dose with granulocyte colony stimulating factor support. Renal function was assessed before treatment, after each IFO cycle and after chemotherapy completion. Acute nephrotubular damage was always observed after each IFO cycle with significant changes of renal tubular enzymesN-acetyl-β-o-glucosaminldase, alanine aminipeptidase, urinary excretion and reduction of tubular reabsorption of phosphate. The appearance of glycosuria was related to the cumulative dose received. Transient and reversible renal tubular acidosis was observed in three patients. WHO grade I renal toxicity was observed in two patients. After chemotherapy completion, persistent mild glomerular and nephrotubular impairment was observed in one patient who had also received aminoglycoside antibiotics due to febrile neutropenia. Persistent and mild glycosuria was documented in another patient. No significant changes compared to baseline values were observed in the remaining patients. We conclude that a chemotherapy regimen with high-dose IFO in young adults pretreated with MTX, cisplatin and standard-dose IFO is feasible with a mild, usually reversible, nephrotoxicity.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The results of treatment of malignant pieural mesothelioma are quite unsatisfactory regardless of the substance or schedule employed. Although some activity is proved for anthracyclines, platinum compounds and alyklating substances, no chemotherapeutic regimen has emerged as a standard of care. Response rates documented in literature are between 10 and 20% for all these regimens. We report about a patient with locally advanced, unresectable pleural mesothelioma treated with the nucleoside analog gemcitabine (2,2-difluorodeoxycytidine). A 54-year-old male patient with unresectable pleural mesothelloma confirmed by thoracoscopic biopsy was treated with seven cycles of gemcitabine (1000 mg/m2on day 1, 8 and 15) over a period of 36 weeks. Restaging by thoracic computed tomography (CT) scan was performed after 8, 20 and 36 weeks. At week 36 after beginning of treatment, the CT scan exhibited a substantial partial remission with a reduction of tumor volume of over 50%. The adverse effects of the therapy were very moderate with a hematotoxicity not exceeding WHO grade I and a mild `flu-like syndrome' during the first three cycles which responded quite well to steroids. The compliance of the patient was excellent and his general condition improved significantly under therapy. Gemictablne seems to be an active drug for the treatment of pleural mesothelioma. Compared to other active regimens it is normally very well tolerated by the patients. Because of these characteristics gemcitabine seems a suitable antineoplastic substance, especially in palliative settings. It would be worthwhile to test its activity in pleural ***mesthelomas in controlled trials.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The makaluvamines are marine natural products that were originally isolated because of their cytotoxicity in a cell-based mechanism screen. They have significant anti-cancer activity in animal models. There is, however, disagreement in the literature as to whether these compounds target topoisomerase II via a clinically relevant mechanism. This work shows that the makaluvamines can induce dose-dependent DNA cleavage via topoisomerase II. For most of the makaluvamines the levels of cleavage are significantly below those achieved by equlmolar concentrations of etoposide. To some extent these results might explain the discrepancies present in the literature.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Dexrazoxane (ICRF-187), which is clinically used to reduce doxorubicin-induced cardiotoxicity, has cell growth Inhibitory properties through its ability to inhibit the catalytic activity of DNA topoisomerase II. A study was undertaken to Investigate whether preincubating Chinese hamster ovary cells (CHO) with dexrazoxane prior to camptothecin treatment resulted in potentiation. Camptothecin is a DNA topoisomerase I poison. It was found that pretreating CHO cells with concentrations of dexrazoxane sufficient to strongly inhibit topoisomerase II for periods from 18 to 96 h resulted in significant antagonism of camptothecin-mediated growth inhibition. Lower concentrations that were sufficient to cause partial Inhibition of topoisomerase II and partial dexrazoxane-mediated cell growth inhibition had little effect on camptothecin-mediated growth inhibition. Neither topoisomerase I protein levels nor camptothecin-induced topolsomerase I-DNA covatent complexes were affected by dexrazoxane concentrations that were sufficient to cause antagonism of camptothecin-induced growth Inhibition. However, under these experimental conditions, dexrazoxane caused a decrease in DNA synthesis. Therefore, results presented here confirm the importance of the DNA synthesis-dependent replication fork Interaction with topoisomerase I-DNA covalent complexes for the expression of camptothecin activity. It is concluded that dexrazoxane and camptothecin analogs should be used with caution in combination chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

A series of molecules with apurinic/apyrimidic (AP) endonuclease activity targeted to abasic sites in DNA, which incorporate an intercalating moiety linked to a purine base by a polyamino chain and recognize and cleave abasic sites in DNA with high efficiency, has been studied. The aim was first to establish whether these compounds were inhibitors of base excision DNA repair, since abasic sites are generated during this process. Using an extension of a recently established methodology, two members of this series have been identified as definite repair inhibitors. Secondly, the potential of using such compounds as sensitizers of alkylating agents has been investigated by determining the cytotoxic activity of these compounds on L1210 cells in culture. A concentration-dependent potentiation of nitrosoureas has been demonstrated, but interpretation is complicated by the inherent cytotoxic properties of the test compounds themselves. Such molecules, however, provide interesting lead compounds for new strategies aimed at enhancing the cytotoxic potential of clinically useful DNA-damaging agents.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

UCN-01 (7-hydroxystaurosporine) and CGP 41 251 (4-N-benzoyl staurosporine), both of which were discovered as protein kinase C selective inhibitors, have entered in phase 1 clinical trials as anti-cancer drugs. In this study, we have directly compared the effects of these drugs as well as staurosporine (STP) on cell cycle progression of A431 human epidermoid carcinoma cells synchronized at M phase by treatment with nocodazole. The nocodazole-synchronized cells progressed from M to G1phase in the absence of the drug, which was accompanied by a decrease of cyclin B1protein expression, disappearance of the complex formation of CDC2with cyclin B1and reduction of the kinase activity. Treatments of the M phase cells with UCN-01, STP and CGP 41 251 at 80% growth-inhibitory concentrations (IC80S) resulted in specific G1block, G2M block and polyploidy, respectively. Decrease of cyclin B1protein expression was partially prevented by treatments with STP and CGP 41 251 but not with UCN-01 at IC30S. Reductions of active complex and kinase activity of CDC2/cyclin B1were also observed in the presence of the three drugs. In addition, augmentation of CDC2 protein tyrosine phosphorylation was induced only when the cells were treated with STP. These observations demonstrated that higher concentrations of UCN-01, STP and CGP 41 251 showed different effects on cell cycle progression as well as CDC2/cyclin B1regulation in A431 cells synchronized at M phase. The data suggest that UCN-01 and CGP 41 251 may act at quite different points on the cell cycle.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Deciopramide (3-chloroprocalnamide) has been identified in previous studies as a representative of a new class of chemosensitizers. In this study, the toxicity and pharmacokinetics of declopramide have been investigated and compared with a structural analog, metoclopramide (MCA). Declopramide has not induced central nervous system (CNS)-related side effects in rats at doses up to 200 mg/kg, whereas MCA does at 12.5 mg/kg. In addition, declopramide did not bind to dopamine D2receptors in subcellular preparations at doses up to 1000 μM, whereas MCA showed affinity at 1 μM. Declopramide bound with affinity to 5-hydroxytryptamine3receptors which are important in controlling vomiting. In contrast to MCA, declopramide has a rapid clearance from serum, a lower tissue concentration (about 15-fold lower than MCA) and a lower oral bloavallability (about 6-fold lower than MCA). However, declopramide was shownin vitroto possess a higher tumor cell absorption rate. One of the main metabolites of declopramide was identified asN-acetyl declopramide. Taken together, these data suggest that the clinical development of declopramide as a sensitizer of radio- and chemotheraples is an improvement over MCA, because it can be administered in a high dose and is devoid of CNS side effects.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID