摘要:

Inhibition of angiogenesis or preventing the outgrowth of new blood vessels towards a tumor is one of the most promising areas of anticancer drug development. Several angiogenesis inhibitors are now on the verge of being tested in clinical trials. This review discusses possible applications of inhibitors of angiogenesis and whether the current methodologies for testing novel anticancer drugs are appropriate to evaluate the efficacy of inhibitors of angiogenesis.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We conducted two consecutive phase I clinical trials to identify the qualitative and quantitative toxic effects of uracil-tegafur (UFT) [Taiho Pharmaceutical Co. Ltd, Tokyo, Japan; (BMS-200604) Bristol-Myers Squibb, Princeton, NJ] administered either on a 5 or 28 day schedule and to determine the phase II trial starting doses for both schedules. Nineteen patients were entered on the 5 day schedule and 23 patients were entered on the 28 day schedule; a minimum of three patients were entered at each dose level studied. In both phase I trials, the daily UFT dose was divided into three doses administered every 8 h. Dose levels examined with the 5 day schedule were 360, 720, 900 and subsequent de-escalation to 800 mg/m2/day. Dose levels studied with the 28 day schedule were 180, 360, 450 and subsequent de-escalation to 400 mg/m2/day. With the 5 day schedule, the dose-limiting toxicity (DLT) was granulo-cytopenia, with four of five patients experiencing grade 4 granulocytopenia at the 900 mg/m2/day dose level. With the 28 day schedule, the DLT was diarrhea, which was noted in three of eight patients treated at 400 mg/m2/day and in three of six patients treated at 450 mg/m2/day. At these dose levels, four of these patients required prolonged hospitalizations for their diarrhea. The toxic effects of UFT are schedule dependent, with marked differences in the toxic effect profile (neutropenia versus diarrhea). With the 5 day schedule, the phase II UFT starting dose is 800 mg/m2/day. On the 28 day schedule, the suggested phase II UFT starting dose is 360 mg/m2/day. Future clinical trials examining the combination of UFT plus oral folinic acid are being conducted to develop oral regimens of therapy for advanced colorectal carcinoma and adjuvant therapy for colon carcinoma.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Forty chemotherapy-naive patients receiving high-dose cisplatin were included in a pilot study of a combination of ondansetron plus metoclopramide as antiemetic therapy. Patients received ondansetron 16 mg plus metoclopramide 0.5 mg/kg in 250 cm3of normal saline i.v. 15 min before cisplatin administration on day 1; then ondansetron 8 mg was given orally b.i.d. and metoclopramide 0.5 mg/kg was given intramuscularly t.i.d. for 4 days. This combination was given to all patients receiving the first cycle of chemotherapy. At the second cycle of chemotherapy all patients received the same antiemetic treatment as above plus methylprednisolone 125 mg i.v. on day 1 and then intramuscularly once a day for 4 days. There were 20 females and 20 males with a mean performance status of 1 (range 0–2) and a mean age of 58 years (range 36–68). Ten patients had ovarian carcinoma, eight patients had uterine adenocarcinoma and 22 had non-small cell lung carcinoma. The mean cisplatin dose was 96 mg/m2. All patients denied significant alcohol consumption. At cycle 1, complete protection against acute emesis was achieved in 22 patients (55%), major protection in 12 cases (30%), minor protection in four patients (10%) and failure in two cases (5%). On the other hand, the efficacy of this combination on delayed vomiting was not striking. For delayed vomiting, complete protection was observed in nine patients (23%), major protection in 13 cases (33%), minor protection in 10 patients (25%) and failure in eight cases (20%). At cycle 2, patients also received methylprednisolone showing complete protection from vomiting in 19 cases (47%) and major protection in 12 cases (30%). Results achieved with ondansetron plus metoclopramide are in the range reported for ondansetron alone in the medical literature. Although this study was not prospectively carried out in a randomized fashion, the results are not suggestive of a possible positive effect of metoclopramide addition to ondansetron. On the other hand, these results stress the role that corticosteroids may play in the control of delayed emesis. Toxicity was predictable and the frequency of side-effects was in the range reported in other studies with ondansetron.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effect of four modulators of multidrug resistance (MDR) on the expression of theMDR1gene was studied in two resistant variants of the KB cell lines, KB V1 and KB A1. This was done using a semi-quantitative assay based on mRNA reverse transcription coupled with polymerase chain reaction of the cDNA obtained. An automatic DNA sequencer was used for the measurement of the fluorescent amplification products and theMDR1signal was compared to that of the β-actin gene of the cells. After 24 h incubation with 15 μM of the modulators,MDR1gene expression was slightly but significantly decreased by two of them, quinine and cyclosporine A, whereas verapamil and S-9788 had very little effect on this parameter. The effect were more pronounced in the KB A1 line than in the KB V1 line. The effect of quinine was studied over a longer time period (4–48 h) and was shown to be maximum at 24 h. These results favor the existence of a direct effect of some MDR reverters, especially quinine, on the expression of theMDR1gene and could partially explain their modulating effect of MDR.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Among the compounds endowed with the capacity to reverse the P-glycoprotein (Pgp)-mediated multidrug resistance of cancer cells, a powerful agent was found to be the cyclosporin D derivative SDZ PSC 833. Afterin vivotreatment with SDZ PSC 833, mice showed a decreased tolerability to cyclosporin A (CsA), but also to ivermectin, a widely used polycyclic lactone pesticide ofStreptomyces avermitillsorigin. The sequels were suggestive of CsA- or ivermectin-induced central nervous system dysfunction; they were interpreted as caused by the neutralization of the Pgp at the blood-brain barrier level, implying that CsA and ivermectin were Pgp substrates. CsA was already known to display both Pgp substrate and Pgp inhibitor properties. It now appears that ivermectin may also inhibit Pgp function. When compared in short-term assays for Pgp function inhibition, which measure the restoration of the retention of two Pgp probes in multidrug-resistant (MDR) cells to their parental (Par) cell levels, ivermectin appeared only a few fold weaker than SDZ PSC 833 in the case of murine monocytic leukemia MDR-P388 cells and nearly as active as SDZ PSC 833 in the case of human lymphocytic leukemia MDR-CEM cells. Therefore, like CsA or FK-506, ivermectin may be both a substrate and an inhibitor of Pgp.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

AG337 is a recent non-classical thymidylate synthase inhibitor with promising activity and manageable toxicity in phase I clinical trials. In this study, we investigated the cytotoxic activity of AG337 alone and in combination with cisplatin in cultured human colon (HT29) and ovarian (2008) cancer cell lines and their derived counterparts selected for their resistance to 5-fluorouracil (5-FU) (HT29–5-FU) and cisplatin (2008C13). We observed that AG337 had potent cytotoxic effects in colon (IC50= 0.17 μM) and ovarian cancer cells (IC50= 0.65 μM). The cytotoxic activity of AG337 was higher than that of 5-FU in the two models. The activity of AG337 was not significatively affected in 5-FU-resistant HT29–5-FU colon cancer cells characterized by an amplification of the thymidylate synthase gene (IC50= 0.27 μM,p= 0.15). Combinations of cisplatin and AG337 exert synergistic activity in both ovarian and colon cancer cells. Interestingly, this synergism was maintained in 5-FU-and cisplatin-resistant cells. Therefore, our data encourage further examination of combinations of AG337 with cisplatin in cancer chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Wakayin is a bispyrroloiminoquinone isolated from aClavelinasp. ascidian by cytotoxicity directed fractionation. Like camptothecin, it has been found to inhibit the topo-isomerase I catalyzed relaxation of supercoiled DNA. Wakayin enhanced cleavage complex formation at the same DNA sequences as camptothecin. Both compounds showed dose-related increases in cleavage complex formation, though wakayin's effect is attenuated at high concentrations. Wakayin is a strong DNA binder. Wakayin also differed from camptothecin in that its cleavage complexes were much less stable than those of camptothecin in 0.5 M NaCI. Again in contrast to camptothecin, wakayin stabilized cleavage complexes poorly, if at all, at 0°C.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Valproic acid (VPA) is a simple branched-chain fatty acid that has anticonvulsant activity and is widely used in the treatment of epilepsy. VPA was found to effect growth and differentiation of human neuroblastoma (NB) cellsin vitroat concentrations that have been achieved in humans with no significant adverse effects. Treatment of UKF-NB-2 and UKF-NB-3 NB cell lines with VPA at concentrations ranging from 0.5 to 2 mM resulted in neuronal morphological differentiation characterized by extension of cellular processes without significant effects on cell viability. Ultra-structural features of VPA-treated cells were consistent with the neuronal type of differentiation. VPA treatment of NB cells was associated with decreased expression of N-myconcoprotein and increased expression of neural cell adhesion molecule in their membrane. Treatment of NB cells with 0.5 mM VPA increased their sensitivity to lymphokine-activated killer lysis. The results indicate that VPA, at non-toxic pharmacological concentrations, arrests the growth, induces differentiation and increases immunogenicity of NB cells through non-toxic mechanisms.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

All-trans-retinoic acid (ATRA) has proven useful in acute promyelocytic leukemia (APL). In order to reduce the side effects and to improve the efficacy of this compound, conventional chemotherapy, and anthracyclines in particular, are frequently added either during remission induction or in consolidation therapy. In this study we aimed at investigating the rationale of the combination of ATRA plus idarubicin in two human leukemic cell lines, HL-60 and K562, that display a different sensitivity to ATRA treatment. The effects of ATRA were compared with those of two clinically active retinoids, 13-cis-retinoic acid (13-cis-RA) and 9-cis-retinoic acid (9-cis-RA). Both in HL-60 and in K562 cells, the majority of the combinations of ATRA and idarubicin were synergistic, while the combinations with 9-cis-RA and 13-cis-RA were more effective in HL-60 and K562 cells, respectively. A 72 h pre-incubation with retinoids was able to further increase the cytotoxicity of ATRA plus idarubicin in the two cell lines. Intracellular idarubicin accumulation was enhanced by retinoids, as demonstrated by a cytofluorimetric method. Our results could contribute to provide a rationale for ATRA plus idarubicin combinations not only in APL but also in acute leukemia of other cytotypes.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A new dosage formulation of 5-fluorouracil incorporated in microspheres (5-FU-MS) was developed for the treatment of peritoneal carcinomatosis. We studied the acute toxicity and side effects of i.p. 5-FU-MS in mice. The 50% lethal dose value for 5-FU-MS was 535.4 mg/kg of 5-FU, which was 2.22 times that of the aqueous 5-FU solution. Deaths occurred 12–17 days after the administration of 5-FU-MS, but within 11 days after the administration of aqueous 5-FU. Thus, lethal toxicity appeared later with 5-FU-MS than with aqueous 5-FU. There were no differences in pathologic findings on autopsy between mice given the two dosage formulations.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID