[Inventory of low dose brachytherapy in anticancer centers. A survey of the radiotherapy group of the National Federation of anticancer centres].
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Brachytherapy↗
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The use of liposomal anticancer agents to determine the roles of drug pharmacodistribution and P-glycoprotein (PGP) blockade in overcoming multidrug resistance (MDR).
Many attempts to circumvent P-glycoprotein (PGP)-based multidrug resistance (MDR) in cancer chemotherapy have utilized PGP blocking agents (also referred to as MDR modulators), which are co-administered with the anticancer drug. This approach is based on the premise that inhibiting PGP function will result in increased accumulation of many anticancer drugs in the tumor cells and restore full antitumor activity. However, co-administration of MDR modulators with anticancer drugs has often resulted in exacerbated toxicity of the anticancer drugs and limited chemosensitization of MDR tumors. These problems appear to be related to MDR modulator blockade of PGP excretory functions in healthy tissues, such as liver and kidney, which markedly reduces anticancer drug clearance properties. Two consequences of these pharmacokinetic interactions are: 1. Increased toxicity due to modulator-induced changes in biodistribution properties of the anticancer drug. 2. Problems interpreting preclinical and clinical data with respect to: a) Are therapeutic improvements due to altered pharmacokinetics or PGP modulation within the tumor cells? And, b) Does decreasing the anticancer drug dose to that which is equitoxic in the absence of the modulator potentially compromise tumor therapy due to decreased anticancer drug levels in the tumor tissue? Although many of the difficulties associated with co-administration of MDR modulators and anticancer drugs are manifested by toxicity effects, it is ultimately the ability to obtain effective antitumor activity against resistant tumors that will determine the utility of chemosensitization approaches. Liposomes appear to be well suited to solve many of the problems noted above that are associated with conventional anticancer drugs and MDR modulators. In view of these considerations, we have hypothesized that inadequate tumor delivery of anticancer agents and selectivity of PGP modulation are primarily responsible for the attenuated therapy of extravascular MDR solid tumors overexpressing PGP. Liposomal carriers have been utilized to provide tumor selective delivery of anticancer agents as well as to circumvent many toxicities associated with these agents by altering the pharmacodistribution properties of encapsulated drugs (1-4). Given the pharmacokinetic changes induced by the MDR modulators on non-encapsulated doxorubicin (DOX), we proposed that liposomes may limit these effects by virtue of their ability to reduce the exposure of encapsulated DOX to the kidneys and alter clearance of DOX in the liver (5,6). These tissues appear to be key factors involved in modulator-induced DOX pharmacokinetic changes (7). In conjunction with these toxicity buffering effects, the effect of PGP blockade on the cellular uptake of DOX in the tumor may be able to be selectively increased using liposomal carriers. This is based on the ability of small liposomes to passively extravasate in tumors (1,2,8,9) as well as their inability to accumulate in healthy susceptible tissues. By studying the toxicity and efficacy properties of liposome encapsulated DOX in combination with the MDR modulator PSC 833 we have been able to demonstrate that two factors play a major role in determining the effectiveness of chemosensitization approaches to overcome MDR; 1) optimizing selective localization of anticancer drug localization in tumor tissue and 2) effective blockade of PGP in tumor cells under conditions that do not compromise anticancer drug accumulation into the tumor. Failure to achieve both of these conditions simultaneously may be expected to result in substantially reduced therapy of MDR tumors.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[The pace of development of approved anticancer agents in Japan].
We investigated the pace of development of 48 approved anticancer agents except for endocrine in Japan up to the end of 1984. Forty-six new anticancer agents on which phase I-II studies had been carried out in our department from 1963 to 1984 and 34 anticancer agents approved in the USA were also referred to. Forty-eight approved drugs consisted of 23 domestic and 25 imported types. It was shown that the ability to develop new anticancer agents in Japan had grown remarkably after around 1970. Fourteen new domestic anticancer agents had been approved after 1973, whereas only 8 imported ones had been approved in the same period. Although more anticancer agents were approved in Japan than in the USA, the marketing of some anticancer agents approved in Japan was discontinued because of the lack of sufficient efficacy on reevaluation study or reduced efficacy compared with newly developed anticancer agents. Anticancer agents approved in the USA had a tendency to be used all over the world and for a long period. Many new domestic anticancer agents approved recently and which are under phase studies are derivatives of fluorinated pyrimidines, cytosine arabinoside and anthracyclines. The development of new domestic anticancer agents with an entirely new mode of action is therefore desirable.
Antineoplastic Agents↗
[The influence of anticancer agents at various stages to induce LAK cell on its cytotoxicity and cell yield. Examination in vitro].
To establish the combination of chemotherapy with adoptive immunotherapy (AIT), using lymphokine activated killer cells (LAK) and/or interleukin-2 (IL-2), author examined the following: 1) Pretreatment with anticancer agents for peripheral blood mononuclear cells (PBMC) and its effect on LAK cell cytotoxicity and cell yield. 2) The addition of anticancer agents in the induction phase to LAK cell and its effect on LAK cell cytotoxicity and cell yield. 3) Pretreatment with anticancer agents to induced LAK cell and its effect on LAK cell cytotoxicity and cell yield. 4) The cytotoxicity of LAK cell against tumor cells treated with anticancer agents. Our experiment has shown that when we take peripheral blood mononuclear cells (PBMC) to induce LAK cells, there is no influence on its LAK cell yield or its cytotoxicity after being harvested as LAK cells, even if there is a maximum concentration of anticancer agents, but in the case of the LAK cell induction phase VDS, CDDP, ADM and MMC have a significant effect on LAK cell yield and on cytotoxicity of LAK cell after being harvested as LAK cells. And it has also been shown that, if there is a maximum concentration of anticancer agents, it has an effect on the induced LAK cell cytotoxicity and on the LAK cell yield after being recultured with IL-2. On the other hand, LAK cell cytotoxicity makes no difference to tumor cells whether they are treated or not with anticancer agents. These results suggest that we can take peripheral blood mononuclear cells to induce LAK cells unrelated to the administration of anticancer agents, and that if we use a combination of chemotherapy with adoptive immunotherapy (IL-2 administration and/or LAK cell adaptation), we should start with the administration of anticancer agents and then administer IL-2 and/or transfer LAK cells after the concentration of anticancer agents decreased under 1/10 of maximum concentration in the blood level of our conventionally clinical use.
Antineoplastic Agents↗
[Health risks of occupational exposure to anticancer (antineoplastic) drugs in health care workers].
In Europe and America, many health care workers have concerns about the risks to their health of handling anticancer drugs. The findings of the risks were reported in the late 1970's, and guidelines for the safe handling of anticancer drugs were established in the 1980's. The conditions of wearing personal protective equipment and of the working environment have improved dramatically as a result of introduction of the guidelines. Furthermore, researches and studies into the health effects of occupational exposure to anticancer drugs have been pursued actively. In Japan, the society of hospital pharmacists established guidelines for the safe handling of anticancer drugs in 1991. Since then, mainly nurses have been concerned about the safe handling of anticancer drugs, but in the medical setting, the present situation surrounding the safe handling of anticancer drugs has hardly changed. In the industrial hygiene field, the safe handling and the occupational exposure to anticancer drugs have been seldom reported and researched. The actual potential hazards to occupational exposure of anticancer drugs have not yet been determined. Nevertheless, the reduction of occupational exposure to anticancer drugs in health care workers has been an important challenge for the industrial hygiene field. In Japan, we need to promote action to spread the use of the appropriate personal protective equipment and the appropriate working environment. We also have to rethink the safe handling of anticancer drugs. We hope that the Japanese government will establish an effective authorized guideline as has been done in Europe and America.
Antineoplastic Agents↗
[Cytotoxic effect of anticancer drug combined with anti-AFP antibody on human hepatoma cell in vitro].
The cytotoxic effect of the anticancer drug, Daunorubicin, combined with the anti human AFP horse antibody (Conjugate) on AFP-producing cells and non producing cells was studied in vitro. No different cytotoxic effects between the conjugate and the anticancer drug alone were observed on non-AFP-producing cells. On the other hand, the conjugate had a much stronger cytotoxic effect than the anticancer drug alone against AFP-producing cells when it was incubated for 24 hours, 5 x 10(-1) micrograms/ml as an anticancer concentration. The cytotoxicity of the conjugate is much stronger than of the comcrued effect of the anticancer drug and the anti AFP antibody (individually). The amount of AFP antibody used was very small. Therefore, the effect of the anticancer drug plus the small amount of AFP antibody was almost the same as the effect of anticancer drug alone. Under these conditions melting of nuclear material (cell death) was remarkable morphologically, and the intracellular anticancer concentration of the conjugate was seven times higher than that of the anticancer drug alone (p less than 0.05). In conclusion, the conjugate has more cytotoxic effect than the anticancer drug alone against AFP-producing hepatoma cells in optimal conditions.
Antibodies↗
Rationale for sequential tamoxifen and anticancer drugs in adjuvant setting for patients with node- and receptor-positive breast cancer.
Since the survival benefit of tamoxifen (TAM) combined with anticancer drugs in treating node- and receptor-positive breast cancer is small, appropriate treatment schedules and the rationale for the combination remains unclear. We examined the effect of estradiol (E2) on sensitivity to anticancer drugs to clarify the survival benefit of tamoxifen combined with anticancer drugs. We used the MTT assay to assess the effect of E2 on sensitivity to anticancer drugs in the E2 receptor-positive and -negative breast cancer cell lines, MCF-7 and MDA-MB-231, respectively. We assessed the expression of apoptosis-related proteins by Western blotting, and evaluated apoptosis using the TUNEL method. Serum levels of E2 were measured using an enzyme-labeled radioimmunoassay in patients with premenopausal breast cancer before and during treatment with tamoxifen. Estrogen administration decreased sensitivity in MCF-7 cells to the anticancer drugs, adriamycin (ADM), mitomycin C (MMC), and paclitaxel (TXL), evaluated as increases in the IC50 values for ADM (4.1-fold), MMC (1.9-fold) and TXL (13.0-fold), compared with those of each drug alone. Estradiol in MDA-MB-231 cells similarly increased the IC50 values for ADM (9.5-fold), MMC (15.6-fold), and TXL (2.4-fold). The decreased sensitivity to these anticancer drugs was associated with the attenuation of apoptosis. Estrogen dose-dependently increased the expression of Bcl-2 protein in MCF-7, but not in MDA-MB-231 cells, and suppressed the expression of Bax and cytochrome c induced by anticancer drugs in association with decreased apoptosis compared with the effect of each drug alone. Phosphorylation of the Bcl-2 protein induced by TXL was decreased in the presence of E2 in MCF-7 cells. Serum levels of E2 were increased in 5 patients without amenorrhea and in 1 patient with amenorrhea after treatment with TAM alone in adjuvant therapy, compared with levels before treatment. Estradiol decreased sensitivity to ADM, MMC, and TXL in MCF-7 and MDA-MB-231 breast cancer cells, and this was associated in part with an increase in the amount of Bcl-2 protein, and decreases in levels of Bax and cytochrome c leading to apoptosis. These results suggest that therapy with TAM and anticancer drugs should be sequentially scheduled with anticancer drugs followed by TAM in an adjuvant setting to treat patients with breast cancer for a potentially improved survival benefit.
Adult↗
Delivery of anticancer drugs.
Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since anticancer drugs are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge. Scientists are working to increase the availability of drug for tumor uptake by 1) delaying the release preparations for long-lasting actions; 2) using liposome-entrapped drugs for prolonged effect or reduced toxicity; 3) administrating inert, non-toxic prodrugs for specific activation at the tumor site; 4) delivering the antibody-mediated drugs; or 5) conjugating site-specific carriers to direct the drug to the tumor target. The latter depends heavily on pharmacokinetic investigations. Some success has been achieved in enhancing the efficacy and reducing the toxicity of drugs. Pharmacokinetic and pharmacodynamic considerations are two areas which have been focused toward the quantitative pharmacological studies of anticancer drugs in this manuscript. This review covers biodistribution and elimination, furnishing information on body clearance and unveiling sites of major metabolism; administration of anticancer drugs via various routes for optimal utilization; intra-arterial infusion for localized tumors, intrathecal, intraperitoneal and intrapleural injection for regional cavity administration. Conventional delivery routes, doses, pharmacokinetics data and elimination routes of therapeutic anticancer drugs are tabled. General approaches for delivery of anticancer drugs in achieving therapeutic improvements are outlined and correlated. Mechanism of drug resistance, and specific changes affecting the delivery of available chemotherapeutic agents, as well as the drugs to restore the sensitivities to agents of resistant tumor cells, are discussed. This monograph covers the developments and progress in the delivery of anticancer drugs in two approaches: the theoretical approach, including pharmacokinetic and pharmacodynamic considerations, therapeutic implications and mechanism of drug resistance, and the practical approach, including the physical, chemical, biochemical and physiological considerations. Among these, the physical approach for the delivery of anticancer agents to target sites (via microparticulate drug carriers: nanoparticles, liposomes, microspheres and activated carbon as well as the magnetic microcapsules) has shown recognizable improvements in prolonging anticancer effects and reducing toxicities. Implantable pumps and reservoirs for regional chemotherapy provide external control of delivery rate. The implanted systems, in general, yield better results than the traditional treatments in the treatment of liver and brain cancer. Chemical approaches for the improvement of drug delivery use prodrugs, biodegradable polymers and macromolecular matrix techniques.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Hepatocellular carcinoma with sarcomatous change: a special reference to the relationship with anticancer therapy.
Among 579 autopsy cases of hepatocellular carcinoma (HCC), 55 cases (9.4%) exhibited a sarcomatous appearance. The incidence of HCC with a sarcomatous appearance has been increasing over the past 17 years. A sarcomatous appearance was found in 20 out of 335 autopsy cases of HCC (5.9%) during the 12 years from 1969 to 1980, and in 35 out of 244 autopsy cases of HCC (14.3%) during the last 6 years, when effective anticancer therapies, such as the one-shot injection of anticancer agents into the hepatic artery (one-shot therapy) and transcatheter arterial embolization (TAE), have become popular. A sarcomatous appearance was found in 20.9% of the cases undergoing anticancer therapy and in 4.2% of the cases not undergoing anticancer therapy. Among the various anticancer therapies, the sarcomatous appearance was most frequent (27.6%) in cases with repeated TAE. Thus, a close relationship between the sarcomatous appearance in HCC and anticancer therapies was suggested. Regarding the development of the sarcomatous appearance, we presume that it may be caused by the phenotypic change of HCC cells caused by anticancer therapy, or that a number of factors, including anticancer therapy, may accelerate the proliferation of the sarcomatous cells existing in the original tumor as one of the histological components. In order to clarify the true nature of sarcomatous lesions in HCC, further histological and biological studies are required.
Carcinoma, Hepatocellular↗
The p53 tumor suppressor gene in anticancer agent-induced apoptosis and chemosensitivity of human gastrointestinal cancer cell lines.
PURPOSE: While the target of many anticancer agents has been identified, the processes leading to killing of the cancer cells and the molecular basis of resistance to the drugs are not well understood. We used human gastrointestinal cancer cell lines and examined how anticancer agents induced cell killing and how the chemosensitivity of these lines was determined. METHODS: Twelve gastrointestinal cancer cell lines were examined for the presence of either a wild-type or mutant p53 gene by direct sequencing. We also determined whether or not cell killing would occur when the cell lines were exposed to anticancer drugs. The sensitivity to the anticancer agents was determined based on colony formation. RESULTS: All 12 gastrointestinal cancer cell lines carried either a wild-type or mutant p53 gene. Three lines, MKN45, MKN74 and COLO320, carried the wild-type p53 gene, and nine carried the mutant p53 gene. When three lines were exposed to the anticancer agents etoposide, doxorubicin (DXR) or 5-fluorouracil (5-FU), cell death ensued. In these cells, the population of cells in G1 phase increased after exposure to high-dose anticancer agents, but cells in G2 phase increased when exposed to low-dose anticancer agents. Our observations support the concept that cells carrying the wild-type p53 gene tend to be sensitive to etoposide and DXR and, in particular, deletion of the p53 function results in a greater resistance to anticancer agents. CONCLUSION: Based on our findings, human gastrointestinal cancer-related cell death apparently occurs via a p53-dependent pathway. A relationship was observed between the induction of cell death and chemosensitivity.
Antineoplastic Agents↗
Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function.
The narrow therapeutic index of anticancer drugs presents a clinical dilemma when these agents are administered to patients with impaired or unstable renal function. The purpose of this review is to (i) describe the nephrotoxicity of certain anticancer drugs, (ii) evaluate the fraction of renal clearance for pertinent anticancer drugs, and (iii) make general recommendations for the dosing of these drugs in the presence of impaired renal function. Pharmacokinetic, pharmacodynamic, and clinical toxicity information was obtained from current scientific and clinical literature. Recommendations for dosage adjustment of drugs is based on their nephrotoxicity, or renal clearance equal to or exceeding 30% of the administered dose. The specific formula used to calculate dosage adjustment of renally cleared anticancer drugs is based on fundamental pharmacokinetic principles. In addition, prospectively validated formulae for the dosage adjustment of specific agents, such as carboplatin are also reviewed. Forty-eight anticancer drugs are reviewed in this report. Nephrotoxicity is associated with 12 of these agents (Table 1). Renal clearance equal to or exceeding 30% of the administered dose is a characteristic of 17 of the drugs studied (Table 2), and a general recommendation for dose adjustment of these anticancer drugs is presented in Table 3. Renal clearance that is less than 30% of the administered dose is a feature of 31 anticancer drugs (Table 4) included in this review. This report provides general guidelines to adjust doses of renally excreted or nephrotoxic anticancer drugs in patients who present with altered renal function.
Antineoplastic Agents↗
[Experimental studies on the dynamics of anticancer agents in transcatheter arterial chemo-embolization. Magnetic resonance imaging using emulsions containing lipiodol and Gd-DTPA].
Transcatheter arterial chemo-embolization with lipiodol and anticancer agents (LP-TACE) is a highly effective therapeutic method for treating liver cancer. It has been difficult, however, to evaluate how lipiodol, an oil, and anticancer agents dissolved in an aqueous contrast medium are retained in tumors. This paper reports the study on the dynamics of anticancer agents administered in LP-TACE both in vitro and in tumor-bearing animals using emulsions produced by mixing lipiodol and adriamycin (ADM) dissolved in Gd-DTPA. The results were as follows. 1) ADM was dissolved in contrast mediums (60% Urografin and Gd-DTPA) and each solution was emulsified by mixing with lipiodol. The emulsion separated into two distinct layers 5 min. after mixing. From this observation it is guessed that lipiodol and anticancer agents also separate in tumors after administration in LP-TACE. 2) Rabbits with VX2 carcinoma implanted in their lower limbs were treated by chemo-embolization and subjected to serial observations for changes in signals on MRI. The signal intensity markedly increased, persisting until one week after administration, when the tumor was resected. This change may have been owing to Gd-DTPA retained in the tumor, indicating that the anticancer agent is not washed out, even after separating from lipiodol, but is retained in the tumor. 3) When ADM was dissolved in Gd-DTPA and intraarterially infused without being mixed with lipiodol, the intensity of the signal on MRI was the same as that in LP-TACE immediately after the administration, and gradually decreased thereafter. This result indicates earlier washout of the anticancer agent when administered without being combined with lipiodol. Quantitative analysis of the tumor resected one week after the treatment also revealed ADM levels with less than 10% of those in LP-TACE, suggesting the possibility of estimating intratumoral concentration of anticancer agents. This was evaluated on the basis of the signal intensity in the tumor using MRI. 4) A comparison of lipiodol accumulation on CT and signal changes induced by Gd-DTPA on MRI suggested that even after separation from lipiodol, the anticancer agent extends to microvessels in the interior part of the tumor.
Animals↗
Amplification of anticancer drug-induced DNA damage and apoptosis by DNA-binding compounds.
A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Most anticancer drugs are known to cause severe side effects. Nontoxic amplification of DNA-cleaving activity of anticancer drugs would enable to reduce drug dose and side effects, leading to development of effective chemotherapy. As a method to approach new cancer chemotherapy, we have investigated the enhancing effects of DNA-binding ligands ("amplifiers"), especially minor groove binders and intercalators, on anticancer drug-induced apoptosis and DNA cleavage, using human cultured cells and(32)P-labeled DNA fragments obtained from the human genes. We have demonstrated as follows: a) DNA-binding molecules (unfused aromatic cations, distamycin A and synthtic triamides) induced amplification of bleomycin-induced DNA cleavage and apoptosis; b) a minor-groove binder distamycin A enhanced duocarmycin A-induced DNA cleavage; c) actinomycin D altered the site specificity of neocarzinostatin-induced DNA cleavage and distamycin A enhanced C1027-induced apoptosis. The mechanism of amplification of DNA cleavage can be explained by assuming that binding of amplifier changes the DNA conformation to allow anticancer drug to interact more appropriately with the specific sequences, resulting in enhancement of anticancer effect. The study on amplifiers of anticancer agents shows a novel approach to the potentially effective anticancer therapy.
Antibiotics, Antineoplastic↗
[Enhancement of cytotoxic effect of anticancer agents of renal cell carcinoma].
BACKGROUND: Human renal adenocarcinomas do not adequately respond to cancer chemotherapy. Their multidrug resistance is mainly conferred by the P-glycoprotein (P-gp). In this study, we analyzed effects of P-gp modulators on enhancement of anticancer activities against human renal cell carcinomas. METHODS: ACHN/ADM human renal adenocarcinoma cells with a high level expression of P-gp and 28 surgical specimens of renal cell adenocarcinomas were recruited. Adriamycin (ADM) and vinblastin (VLB) were used as anticancer drugs, and verapamil (Ver) and cyclosporin A (CsA) were as P-gp modulators. The chemosensitivity was determined by the ATP-assay. RESULTS: Ver and CsA exhibited 1.5-fold and 6-fold increase, respectively, in the anticancer activities of ADM against ACHN/ADM cells. The anticancer activities of VLB were also enhanced by the modulators; 7-fold for Ver and 11-fold for CsA. In the chemosensitivity test of clinical specimens, the cancer for which the viability of the cells assessed by the ATP-assay was 50% or less than 50% after exposure to the anticancer drug with or without a P-gp modulator was defined as sensitive to the drug. Of the 14 clinical specimens exposed to anticancer drugs without Ver, only 3 tumors and 1 tumor were sensitive to ADM and VLB, respectively, whereas with Ver, 6 tumors and 4 tumors were sensitive to ADM and VLB, respectively. Of the other 14 clinical specimens exposed to anticancer drugs without CsA, only 3 tumors and no tumor were sensitive to ADM and VLB, respectively, whereas, with CsA, 9 tumors and 6 tumors were sensitive to ADM and VLB, respectively. CONCLUSION: This study indicate that Ver and CsA have effects on enhancement of the anticancer activities of ADM and VLB against human renal adenocarcinomas. The addition of Ver or CsA to chemotherapy will be a potential circumvention of P-gp-mediated multidrug resistance of renal cell adenocarcinomas.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with cirrhosis: evaluation of two kinds of dosages of anticancer drugs and analysis of prognostic factors.
BACKGROUND/AIMS: To evaluate the efficacy of TACE (transcatheter arterial chemoembolization) with use of low-dose versus conventional-dose anticancer drugs in hepatocellular carcinoma patients with cirrhosis and to analyze their prognostic factors. METHODOLOGY: Eight-two patients with unresectable hepatocellular carcinoma underwent super-selective TACE. Patients in group A (n = 40) received low-dose anticancer drugs. Patients in group B (n = 42) were given conventional-dose of anticancer drugs. Tumor response and survival time in the two groups were compared. Cox proportion-hazards modeling was used to evaluate the relative importance of prognostic variables. RESULTS: There was no significant difference between the two groups in initial tumor response (P < 0.05). The median survival in all patients was 18 months (mo). The median survival in groups A and B were 20 mo and 16 mo respectively. The cumulative survival rates at 6, 12, 18, 24, 30 mo were 68.4%, 57.6%, 38.4%, 26.6%, 19.9% in group A, and 62.6%, 43.8%, 31.9%, 26.5%, 26.5% in group B. There was no significant difference in survival between the two groups (P > 0.05). The factors influencing prognosis were Child-Pugh scores (P < 0.0001), tumor thrombus in the portal vein (P < 0.0001), tumor size (P < 0.0001), method of embolization (P < 0.0001), TACE times (P < 0.001). The dosage of anticancer drugs employed in TACE was not relevant to the survival rates (P = 0.883). CONCLUSIONS: TACE with use of large-dose anticancer drugs does not significantly enhance the anticancer effects and survival compared that with lowdose anticancer drugs. The therapeutic effect of TACE was mainly attributed to embolization of the artery rather than to anticancer drugs.
Adult↗
[Safety awareness of anticancer drug handling among Japanese nurses].
OBJECTIVES: The purpose of this study was to investigate Japanese nurses' awareness of the adverse effects of occupational exposure to anticancer drugs and safe handling, as well as their associations. METHODS: A self-rating questionnaire was mailed to 939 nurses in 107 university hospitals, 13 cancer-special hospitals, and 193 general hospitals with over 300 beds and at least five or more clinics in Japan. A total of 571 female nurses responded to the questionnaire. RESULTS: About 40% of the nurses were not at all aware of the potential adverse effects of occupational exposure to anticancer drugs. Eighty-eight percent of the nurses prepared anticancer drugs in the hospital wards; in most cases, nurses, not doctors or pharmacists, transported and administered such drugs to cancer patients. Regarding safety, 39% of the nurses took protective countermeasures against anticancer drugs; 15% paid special attention to the handling environment; 10% had guidelines for the handling of anticancer drugs; and, only 7% took countermeasures with body fluids or linen handling of cancer patients. Although 82% of the nurses were concerned about the potential health effects of occupational exposure, 75% or over did not know whether the exposure might affect their future health or progeny. Awareness of adverse effects was significantly related with precaution in anticancer drug handling, for which 95% of the nurses stated a desire for special education and training. CONCLUSIONS: Approximately 60% of Japanese nurses are aware of the risk of occupational exposure to anticancer drugs, but this might be an overestimate because of the sampling bias. Since only small numbers of nurses take sufficient safety precaution, programs for education and training for safe handling of anticancer drugs are crucial.
Adult↗
[Timeline from discovery of 5-FU to development of an oral anticancer agent S-1 and its drug concept].
C. Heidelberger et al left great gifts to us. Approximately 50 years have elapsed since their discovery of 5-FU in 1957 before eventually elucidating the mechanisms by which the drug exerts its pharmacological actions and provokes its adverse reactions. Namely, 5-FU is a typical antimetabolite with strong time dependency, and continuous venous infusion(CVI) is considered to be its optimal regimen. The following facts may be mentioned to explain why such a long period of time has been spent to reach this level of research: 1) 5-FU, when administered to the living individual, is mostly inactivated by hepatic catabolic enzymes without delay and is then excreted in the urine, thus making it difficult to precisely analyze the relationship of blood 5-FU concentrations with concentration persistence, anticancer activity, and adverse reactions; and 2) unlike other anticancer agents, an antimetabolite 5-FU separately generates metabolites which show anticancer activity and adverse reactions, as well as metabolites which show adverse reactions only. For the last 30 years, we paid attention especially to 5-FU among chemotherapeutic agents for cancer and have sought for a long-lasting therapeutic modality which maintains quality of life of the patient and patient compliance by considering the balancing between its effects and adverse reactions. Consequently, we concretized an innovative therapeutic drug, TS-1 (S-1). We have a long history of research before developing S-1, which is represented by a series of investigations consisting in the developments of Futrafur (FT)--an oral anticancer agent of a 5-FU derivative (prodrug)-in 1970 subsequent to the above discovery of 5-FU, of UFT(FT: Ura=1 : 4) in 1976, and of S-1 in 1999. To date, we took the initiative in the world to devise S-1, the first self-rescuing concept(SRC)-based anticancer agent with dual actions, i.e., enhancement of pharmacological actions of 5-FU and reduction of its adverse reactions, by making use of the biochemical and enzymological properties of 5-FU and by combining FT, which is gradually converted to 5-FU in the body, with a 5-FU's effect-enhancing substance and a 5-FU's adverse reaction-reducing substance. S-1 is an oral anticancer agent in capsule, in which the following 2 modulators for 5-FU are combined to FT: one is CDHP(5-chloro-2,4-dihydroxypyridine) which increases blood concentrations and enhances pharmacological actions of 5-FU by potently inhibiting the degradation of 5-FU; and another is Oxo(potassium oxonate) which is localized in the mucosa of the gastrointestinal (GI) tract after oral administration and reduces GI toxicities provoked by 5-FU. S-1 is an oral anticancer agent in which these 3 components, FT, CDHP, and Oxo, are combined at a molar ratio of 1 : 0.4 : 1. Our conception to develop an SRC-based therapeutic drug and the preclinical concepts validated by numerous basic studies were demonstrated also in the clinical trials. In January 1999, S-1 was approved for the treatment of advanced and recurrent gastric cancers through the priority review system. From 2001 to 2005, S-1 was approved for the treatment of head and neck cancer, colon cancer, non-small cell lung cancer, and breast cancer. S-1 has been applied to acquire its expanded indications for the treatment of pancreatic cancer and biliary tract cancer. We are confident that the combined regimen of S-1 with other anticancer agents and with other therapeutic modalities will contribute to the routine medical practice of cancer treatment in the future.
Administration, Oral↗
[Effect of combinations of anticancer drugs with interferons on human lung cancer cell lines evaluated by human tumor clonogenic assay].
Using the double agar layer method of human tumor clonogenic assay, the anticancer effect of different combinations of anticancer drugs and interferons was tested on 3 lung cancer cell lines, PC-13, PC-14, and Calu-1. The anticancer drugs and the concentrations used in this study were cisplatin (1.0 microgram/mL), adriamycin (1.0 microgram/mL), mitomycin C (0.2 microgram/mL), VP-16 (5.0 micrograms/mL) and 5-FU (5.0 micrograms/mL). Three kinds of interferon, alpha, beta and gamma in 5,000 units/mL, were tested in combination or in sequence with other anticancer drugs on lung cancer cell lines. The results demonstrate an enhanced anticancer effect on PC-14 only with sequential or simultaneous combination of VP-16 with alpha, beta and gamma interferons; and on Calu-1, only with sequential use of adriamycin and beta-interferon. Our results indicate that there is no unique way of combining anticancer drugs and interferons which can obtain an enhanced anticancer effect on all lung cancer cell lines. The best combination of interferon and anticancer drugs seems to be influenced by the biological characteristics of the cancer cells.
Antineoplastic Combined Chemotherapy Protocols↗