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PubMed1994

[Promotion of hematogenous metastasis in relation to endothelial cell injury by treatment with anticancer drugs].

It has been reported that anticancer drugs at high concentration increase experimental hematogenous metastasis owing to endothelial injury. In this study, we evaluate the effects of anticancer drugs at clinical doses on endothelial cells in the process of metastasis. To do so, we have developed in vitro assay methods which can assess endothelial cell retraction and barrier function against invasion by tumor cells. 5-FU at clinical doses caused neither retraction nor decreasing barrier function, however, ADR and MMC caused retraction of endothelial cells and increased invasion by tumor cells. These effects reached maximum 12 hours after treatment with ADR or MMC, and the number of liver metastases was also significantly increased in in vivo study when tumor cells were injected via portal vein at 12 hours after administration of ADR. It was suggested that some kinds of anticancer drugs at the clinical dose may increase hematogenous metastasis in treatments.

Animals↗

PubMed1994

[Study of in vitro cancer sensitivity of anticancer drugs by SDI (succinate dehydrogenase inhibition test)].

To clarify the effect of fibroblast mixture in in vitro sensitivity test using SDI method. I have investigated the influence of fibroblast on the anticancer sensitivity test in a colon cancer cell line. The anticancer drugs, such as MMC (mitomycin C), CDDP (cisplatin) and 5-FU (5-fluorouracil) were contacted with colon cancer cells at 8 different concentrations on the intervals from 24 to 168 hours. The drug sensitivity of cancer cells in mixture of fibroblast was influenced by the kind of anticancer drugs, sensitivity of fibroblast itself, and the difference of sensitivity of cancer cell and fibroblasts. With the increase of percentage of fibroblast, the sensitivity of cancer cells became almost equivalent to that of fibroblast in 5-FU. But the sensitivity was not influenced by MMC or CDDP. And the difference of sensitivity was within about 27% by using 5-FU when the cancer cell ratio is 50%. Drug sensitivity of cancer cells was greatly influenced by drug concentration and contact time. Although the optimal contact time of sensitivity test depended on the kinds of drugs, 72 hours was considered to be optimal.

Cisplatin↗

PubMedDate not supplied

Susceptibility of human colon carcinoma cells to anticancer drugs is enhanced by L-histidinol.

The effects of L-histidinol on cell cycle transit and anticancer drug susceptibility of four cultured human colon carcinoma cell lines have been examined. The lines studied included two lines, SW480 and SW 620, which were derived from the same patient as a grade III adenocarcinoma of the colon and a lymphatic metastatic form of colon carcinoma, respectively, as well as the human colon adenocarcinoma lines HT-29 and WiDr. L-Histidinol accentuates the vulnerability of all of these human carcinoma lines to several different classes of anticancer drugs, including 5-fluorouracil, the most effective and most commonly used single agent for metastatic colon carcinoma. The ability of L-histidinol to accentuate the sensitivity of these colocarcinoma lines to anticancer drugs, including those which are cell cycle-dependent, is in apparent contradiction to the finding that L-histidinol markedly slows cycle transit in all lines tested.

Adenocarcinoma↗

PubMed1994

Interaction of amino acids with a non-homologous series of anticancer drugs.

The interaction of amino acids with 14 commercial anticancer drugs was studied by charge-transfer reversed-phase thin-layer chromatography and the retention matrix was evaluated by principal component analysis. The majority of amino acids had a negligible effect on the retention of anticancer drugs. Only dicarboxy amino acids and Trp exerted a considerable impact on the retention of drugs, indicating the involvement of hydrophilic forces (probably hydrogen bond formation) and stacking interactions in the binding of drugs to amino acids. Stepwise regression analysis proved that both the pI value of amino acids and the pK value of the amino acid side chain significantly influence the strength of interaction. The findings support the hypothesis that the binding of anticancer drugs to proteins may involve both hydrophilic forces occurring between the corresponding polar sub-structures of drugs and amino acids and stacking interactions between the various ring structures. The relative importance of these interactions depends on the character of the amino acid residue and the chemical structure of drugs.

Amino Acids↗

PubMed1994

[Clinical evaluation of granisetron injection against nausea and vomiting induced by anticancer drugs including cisplatin].

The antiemetic effect and safety of granisetron injection on nausea and vomiting induced by anticancer drugs were studied in the patients treated with anticancer drugs including 50 mg/m2 or more of cisplatin (CDDP). Granisetron is already on the market, and drip infusion of granisetron at 40 micrograms/kg has been used widely in clinical practice. In this clinical investigation, a simpler administration method of its slow (30 to 60 seconds) intravenous injection at 40 micrograms/kg just before CDDP administration was used. The clinical efficacy, safety and usefulness against nausea and vomiting were investigated in 22 patients, and the study medication was assessed as "remarkably effective" or "effective" in 16 patients (72.7%). Neither adverse experience nor abnormal laboratory test value was reported. In the usefulness rating, the study medication was assessed as "extremely useful" or "useful" in 16 out of 22 patients (72.7%). The above results have shown that the slow intravenous injection of granisetron has an excellent antiemetic effect on nausea and vomiting induced by anticancer drugs including CDDP and a high degree of safety.

Adult↗

PubMedDate not supplied

Intracavitary treatment of malignant ascitic carcinomatosis with oily anticancer agents in rats.

The anticancer effects and pharmacokinetics of intraperitoneal (ip) injection were determined for doxorubicin (DOX) dissolved in a lymphographic oily contrast medium, Lipiodol Ultrafluid (Lipiodol) (DOX/Lipiodol), using AH 130 ascitic tumor in rats. A high percentage (50%) of long-term survivors (cure) was observed with only a single ip injection of the DOX/Lipiodol on the seventh day after tumor inoculation, by which time the tumor ascites accumulated to a level similar to that seen clinically. The cure rate of this lipid formulation was much better than that for DOX dissolved in saline (DOX/saline) (17%). An immunopotentiating agent, Picibanil, given in 1 KE (clinical unit) or 5 KE doses was no better than the saline group, indicating that the above effect was not a result of immunopotentiation by Lipiodol. The severity of toxic side effects of DOX was also reduced by lipid solubilization. Pharmacokinetic study showed that DOX/saline was absorbed rapidly into the blood stream from the peritoneal cavity, whereas DOX/Lipiodol was retained in the ascites at a higher concentration for a much longer time. Thus the present results suggest that lipid formulations of anticancer agents have augmented therapeutic efficacy by intracavitary injection. The lipid formulations show increased stability in and prolonged slow release from the lipid milieu. Thus this therapeutic tactic of using oily anticancer agents appears to be promising for the control of pleural and peritoneal carcinomatoses.

Animals↗

PubMed1993

[A preliminary assessment of the efficacy of anticancer measures in malignant stomach neoplasms].

Anticancer prophylactic and treatment measures are approved initially among small populations contingents and, hence, their results are not essentially effecting demographic values. Changes of the state of selected contingents are evaluated by means of lethality or survival values. On the example of gastric cancer patients survival, the authors determine the period of observation necessary for preliminary evaluation of the efficiency of anticancer measures. During 5 years there was no clear change of survival of patients with gastric cancer of stage I-II (P > 0.05). The duration of the period of statistically valid reduction (P < 0.001) of the survival of patients with gastric cancer (stage III-IV) was two years. Thus, changes of the level of two year survival in patients advanced gastric cancer under the effect of anticancer measures may be used for express-evaluation of these measures.

Female↗

PubMed1993

[Clinical evaluation of granisetron for nausea and vomiting induced by anticancer drugs--multi-centered placebo-controlled double-blind comparative study].

A placebo-controlled double-blind comparative trial was conducted to objectively assess the antiemetic effect on nausea and vomiting induced by anticancer drugs including cisplatin (CDDP) and safety of granisetron tablet (2 mg). In the present trial, single oral administration of the trial drug was performed one hour before the start of CDDP administration. 1) In clinical efficacy, the drug was assessed as "remarkably effective" or "effective" in 76.9% (30/39) in G group and 15.2% (7/46) in P group. The drug was assessed as "extremely useful" or "useful" in 84.6% (33/39) and 13.3% (6/45) in respective groups. These results indicated that G group was statistically significantly better than P group in these parameters. 2) In safety rating, the drug was assessed as "safe" in 100% (49/49) in G group and 95.9% (47/49) in P group, indicating equivalent levels between these groups. 3) The antiemetic effect of granisetron tablet was not dependent on patient's background factors including sex, P.S., the dose of CDDP and the number of anticancer drugs concomitantly used with CDDP. 4) The clinical effect of single oral administration of granisetron tablet (2 mg) persisted for approximately 24 hours. 5) In terms of the safety of the trial drug, there was no adverse event or abnormal laboratory fluctuation which might pose a clinical problem. From the above results, it was concluded that single oral administration of granisetron at a dose of 2 mg could suppress nausea and vomiting induced by the administration of anticancer drugs.

Administration, Oral↗

PubMed1996

[Anticancer agents and apoptosis].

We reviewed recent investigations on apoptosis related to anticancer chemotherapy. The study of programmed cell death, apoptosis, has become one of the main stream in cellular biology, particularly in immunology, developmental biology and oncology. To determine whether the apoptotic cell death induced by anticancer agents could be inhibited by bcl-2 oncogene, we established a bcl-2 transfected human small cell lung cancer cell line, SBC-3/Bcl-2. SBC-3/Bcl-2 showed higher resistance to ADM, CPT-11 and MMC compared to the parental line SBC-3. Agarose gel electrophoresis showed typical DNA fragmentation of SBC-3 following treatment with CPT-11 or MMC. In contrast, the same concentration of the drugs did not induce DNA fragmentation in SBC-3/Bcl-2. However, there was no difference in sensitivity to CDDP, VP-16, ACNU, MTX and Taxol between SBC-3 and SBC-3/Bcl-2 (Ohmori T, et al: Biochem Biophys Res Commun 1993). These results suggest that bcl-2 can modulate the cytotoxicity of some anticancer agents by inhibiting the process of apoptosis. We speculate that some apoptotic pathways are bcl-2-dependent and others bcl-2-independent.

Animals↗

PubMed1996

[Current status and problems in clinical trial for new anticancer drug in Japan].

Results of clinical trials for 28 anti cancer drugs in 20 pharmaceutical companies were analyzed to describe current status and problems in clinical trial for new anticancer drug in Japan. Phase I studies have been carried out in one to 19 institutes (median; 12), and in the period of 4 to 35 or more months (median; 13 months). Median number of patients entered into phase II studies was 2.9 per institute. Out of 21 drugs which finished the clinical trial, 4 were approved, 6 were made an application for approval, and 11 were discontinued the clinical development. Following problems are arisen in clinical trial for anticancer drug in Japan. Decision network for clinical development of new drug should be organized. Development of derivatives should be prudently done because it is difficult to overcome the parent product in efficacy. Phase I institutes for new anticancer drug evaluation should be designated by authority. Decision of sample size, patient selection, quality control, and informed consent are critical problems in clinical trials for new drug.

Antineoplastic Agents↗

PubMed1996

[Current problems in development of new anticancer agents for new molecular targets].

In this report, we present some current problems in the development of new anticancer agents for new molecular targets in the development process: basic research, developing research and clinical trials. Also new proposals are made to solve these problems from our corporate point of view. It will be necessary to work out new rational methods to evaluate toxicity and efficacy considering the mechanisms and pharmacokinetics of drugs to develop new anticancer agents. Changes in clinical evaluation criteria for antitumor agents, from tumor size to survival time an improvement of QOL, will mean increased costs and a longer time for clinical trials. Given these conditions, it will be necessary for companies to co-operate with public research institutes in order to develop new anticancer agents, and to revise the guidelines and systems of clinical trials.

Antineoplastic Agents↗

PubMed1996

Preclinical pharmacology of the natural product anticancer agent bryostatin 1, an activator of protein kinase C.

Bryostatin 1, a natural product anticancer agent isolated from a marine bryozoan, has been shown in tissue culture to activate protein kinase C. This agent has recently undergone Phase I testing in humans given either as a bolus i.v. injection or a continuous infusion. To understand how bryostatin 1 might be used best as an anticancer agent, a study of the pharmacokinetics, tissue distribution, metabolism, and elimination of bryostatin 1 in mice was undertaken, using [C26-3H]-labeled bryostatin 1. Following i.v. administration, the plasma disappearance curve for bryostatin 1 could be described by a two-compartment model, with half-lives of 1.05 and 22.97 h, respectively. In contrast, the plasma disappearance curve for bryostatin 1 administered i.p. was better described by a first order absorption one-compartment model, with an absorption half-life of 0.81 h and an elimination half-life of 28.76 h, respectively. The majority of radioactivity in plasma was associated with the intact drug for up to 24 h after dosing. In the first 12 h after i.v administration, urinary excretion represented the major pathway of elimination, with 23.0 +/- 1.9% (mean +/- SD) of the administered dose excreted. Within 72 h after i.v. administration, approximately equal amounts of radioactivity (40%) were excreted in feces compared to urine. Bryostatin 1 was widely distributed in many organs but concentrated in the lung, liver, gastrointestinal tract, and fatty tissue. The concentration in the gastrointestinal tract, along with the fecal excretion, suggests the possibility of enterohepatic circulation of this drug. In summary, this study demonstrates that bryostatin 1 is relatively stable in vivo, widely distributed but concentrated in some major tissues, and rapidly excreted first through urine and at later times through the feces. The data from this animal study should be useful in the design of future human trials with this anticancer drug.

Animals↗

PubMed1996

[Study on clinical effect of a continuous intravenous infusion of azasetron against nausea and vomiting induced by anticancer drugs including CDDP].

Azasetron, a selective 5-HT3 receptor antagonist, has been previously shown to be highly effective in the prophylaxis of nausea and vomiting induced by anticancer drugs and is widely used in the clinical setting in Japan. In order to improve the antiemetic effect of azasetron, we designed a continuous intravenous infusion method of this drug and compared the antiemetic effect of this method with that of standard bolus intravenous injection on nausea and vomiting associated with anticancer drugs including 75 mg/m2 cisplatin (CDDP). A continuous group is intravenous bolus injection of 2.5 mg azasetron followed by 7.5 mg continuous intravenous infusion for 24 hrs, and a bolus group is intravenous bolus injection of 10 mg azasetron. The inhibitory effect on nausea of the continuous group was significantly superior to those of the bolus group on day 3 and 4 (p < 0.05) and inhibitory effect on vomiting of the continuous group was significantly superior to those of bolus group on day 2 (p < 0.05). No adverse effects were observed in either group of this study. From these data, continuous intravenous infusion of azasetron was considered to be highly effective in prophylaxis of nausea and vomiting induced by anticancer drugs.

Adult↗

PubMed1997

[Introduction of anticancer agents to phase I clinical trials].

Because about half of patients with cancer could not be cured by the present standard therapy, new effective anticancer agents should be developed and introduced at the clinical level. However, there are several important and specific issues from scientific, medical, statistical, and ethical viewpoints in the design and conducting of phase I clinical trials of new anticancer agents. Clinical safety data management is critically important in phase I clinical trials. Phase I clinical trials are vastly different from phase II or III clinical trials in terms of these issues. This paper discusses issues of early anticancer drug development to be solved or improved.

Antineoplastic Agents↗

PubMed1997

[Anticancer drug-induced colitis--case report and review of the literature].

We encountered two chemotherapy cases related to anticancer drug-induced colitis. Case 1 was a 35-yo-female with a recurrence of ovarian cancer. She was treated with intraarterial infusion consisting of continuous 5-fluorouracil (250 mg/day 5 days/week x 4) following low-dose consecutive cisplatin (20 mg/day 5 days/ week x 1). The catheter was inserted into the abdominal aorta about 2 cm above the carina of the common iliac arteries. Six weeks after the start of chemotherapy, severe abdominal pain and melena occurred. Case 2 was a 68-yo-female with an endometrial cancer recurrence. The same intraarterial chemotherapy used in case 1 was was initiated. Four weeks after the start of chemotherapy, before intraarterial infusion of CDDP, she suffered from constipation and than diarrhea, abdominal pain and melena. Both cases were diagnosed as anticancer drug-induced colitis with the pathological findings from colon biopsy and the clinical course, and improved in about 1 month with the discontinuation of intraarterial infusion, fasting and TPN. Intraarterial infusion of only CDDP caused both patients no intestinal symptoms, so it is supposed that intraarterial infusion of 5-fluorouracil induced the colitis. Anticancer drug-induced colitis should be taken into consideration as a rare but possible course of chemotherapy-related complication with intraarterial infusion of 5-fluorouracil.

Adult↗

PubMed1997

[Glutathione levels in human colon cancer cell line M7609 following culture in a low sulfur amino acid medium and its sensitivity to various anticancer drugs].

Glutathione levels in human colon cancer cell line M7609 and its sensitivity to anticancer drugs were investigated in a complete medium RPMI-1640 (medium A) and an incomplete medium (medium B), which was prepared by removing glutathione and sulfur amino acids from medium A. Four different medium conditions were prepared by combining a medium A and a medium B; a medium of 100% medium A (Control), a 50:50 mixture medium of medium A and medium B (Condition 2), a 20:80 mixture medium of medium A and medium B (Condition 3), and a 10:90 mixture medium of medium A and medium B (Condition 4). The cells were cultured in each medium for 14 days, and intracellular levels of glutathione were determined to estimate the cell sensitivity to anticancer drugs. There were no significant differences in glutathione levels among the cancer agents in condition 2, as compared to those in the control. In condition 3, the reduced glutathione levels were decreased to 23.1%, where CDDP, ADM, MMC and melphalane showed 2.5, 2.2, 1.8 and 1.5 times greater antitumor activity than in the control, respectively. In condition 4, cell proliferation was too low to collect adequate cells for glutathione determination. These results demonstrated that the decrease in cellular glutathione concentration with this method might enhance the cytotoxic effects of anticancer drugs.

Amino Acids, Sulfur↗

PubMed1997

[Clinical effect of two azasetron treatment methods against nausea and vomiting induced by anticancer drugs including CDDP].

Azasetron, a selective 5-HT3 receptor antagonist, has been previously shown to be highly effective in the prophylaxis of nausea and vomiting induced by anticancer drugs, and is widely used in the clinical setting in Japan. In order to improve the antiemetic effect of azasetron, we designed two treatment methods using this drug and compared the antiemetic effect of this method with that of standard bolus intravenous injection on nausea and vomiting associated with anticancer drug including 75 mg/m cisplatin (CDDP). The two-treatment group received an intravenous bolus injection of 5 mg azasetron before and 8 hours after the start of chemotherapy, and a standard group was given an intravenous bolus injection of 10 mg azasetron only once a day. The inhibitory effect on vomiting in the two-treatment group was significantly greater than those of the standard group on day 1 and 2 (p = 0.0458, p = 0.0273), and the inhibitory effect on nausea of the two-treatment group tended to be superior those of the bolus group on day 2 (p = 0.0533). No adverse effects were observed in either group of this study. From these data, the two-treatment approach was considered to be highly effective in prophylaxis of nausea and vomiting induced by anticancer drug.

Adult↗

PubMed1997

[Clinical evaluation of 2-mg granisetron tablet for nausea and vomiting induced by anticancer drugs including cisplatin].

The antiemetic effects on nausea and vomiting induced by anticancer drugs and safety of a 2-mg granisetron tablet were studied in cancer patients, particularly in the field of gynecology, who had been treated with anticancer drugs including cisplatin (CDDP) at 50 mg/m2 or more. The 1-mg granisetron tablet is already commercially available and used widely in clinical practice by oral administration of two tablets per dosage. In this investigation, the clinical efficacy, safety and usefulness of a 2-mg tablet, which can be taken more easily, were studied. The 2-mg granisetron tablet was judged to be "remarkably effective" or "effective" for nausea and vomiting in 22 (66.7%) of 33 patients. For safety, neither adverse experiences nor abnormal laboratory values were judged to be of clinical significance. The 2-mg granisetron tablet was considered "extremely useful" or "useful" in 22 (66.7%) of 33 patients. The above results confirmed the excellent antiemetic effect on nausea and vomiting induced by anticancer drugs including CDDP and the high degree of safety of a 2-mg granisetron tablet.

Adult↗