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F Fujita

Publications and source records attributed to F Fujita.

At least 55 records · Page 3Linked to original sources
PubMed1987

[Evaluation by multiple regression analysis of factors influencing the chemosensitivity of human tumors xenografted into nude mice].

The chemosensitivity of human cancer lines is thought to be expressed as a result of contributions by various interacting factors. Multiple regression analyses were performed in order to clarify the weighting of factors responsible for the chemosensitivity of 15 human cancers xenografted into nude mice. Inhibition rates of 11 anticancer agents predetermined for each line of human cancer were used as the criterion variables. As the explanatory variables, 9 parameters characteristic of each cancer or cancer-bearing mouse were selected as follows; grade of differentiation, vascularity, percentage necrosis, volume doubling time, labeling index, LDH activity, tissue/serum LDH ratio, thymidine phosphorylase activity and serum CEA. By applying this analysis with stepwise deletion, the estimated multiple regression equations for drug sensitivity were clarified for each drug. Although all equations were composed of different factors and their partial repression coefficients varied from drug to drug, those among analogous drugs such as FT-207 and UFT, or MMC and M-83 had similar factors. The equations for M-83, ACNU and ADR consisted of a number of parameters with a sufficiently high coefficient of determination of over 80%. Even in cases of MXT that showed no significant factor upon simple correlation analysis, an equation with 7 factors revealed a coefficient of determination of 0.83. The estimated values of effectiveness for these drugs showed remarkable coincidence with each actual value. For some drugs, the in vivo mode of action was inferred through this analysis.

Animals↗
PubMed1987

[Combination chemotherapy with 3 or 4 drugs on human breast and gastrointestinal cancer xenografts in nude mice (II)].

Because of the limited effects of single-agent chemotherapy for solid tumors, combination therapy was employed in an attempt to enhance the clinical effects. Following our former report in which the combination effects of mitomycin C (MMC) and 5'-deoxy-5-fluorouridine (5'-DFUR) were clarified, combined applications of 4 drugs, vindesine (VDS), methotrexate (MTX), cisplatin (CDDP) and 5'-DFUR against 3 lines of human breast cancer (H-62, H-31, H-71), and one line each of gastric cancer (H-55) and colon cancer (H-110) xenografted into nude mice were evaluated in comparison with CAF (cyclophosphamide, adriamycin and 5-FU) therapy which is commonly used for breast cancer. Treatment was initiated in groups of 7 mice each when the mean tumor volume of subcutaneous tumors had reached about 100mm3, and the therapeutic effect was evaluated in terms of the inhibition rate (I.R.). A synergistic effect is said to exist when the combination therapy is superior to each single drug therapy at the maximal tolerated dose. Combination therapy with 3 drugs (VDS, CDDP and 5'-DFUR) or 4 drugs (VDS, CDDP, MTX and 5'-DFUR) achieved an I.R. of over 98%, i.e., a marked effect with tumor shrinkage, in 3 lines of tumors (H-55, H-31 and H-62). Moreover, remarkable effects were shown even in the other 2 lines which were insensitive to every single-agent therapy, the I.R. values being 85.7% (H-71) and 78.5% (H-110). A synergistic effect was obtained in 3 of the 5 lines examined. These combination therapies were histologically superior to therapies employing each single-drug therapy or CAF therapy. The side effects for combination of these 3 or 4 drugs evaluated by body weight loss were transient and equivalent to maximal dose of VDS or CDDP. Clinically, it is thought that these combined therapies of 3 or 4 drugs will bring about a considerable response in practice.

Animals↗
PubMed1987

[Effects of alternating chemotherapy with 2 non-cross-resistant drug combinations on human alimentary and breast cancer xenografts in nude mice].

Despite the recent advances made in the development of anticancer drugs, any single chemotherapy treatment has only limited effects on cancers of the stomach, colon and breast, so that the combined use of multiple drugs is necessary for the treatment of solid tumors. In our previous studies with human gastrointestinal and breast cancers xenografted into nude mice, combination therapy with mitomycin C (MMC) and 5'-deoxy-5-fluorouridine (5'-DFUR) [I] or cisplatin (CDDP), vindesine (VDS) and 5'-DFUR [II] produced higher response rates than single-agent therapy with any one of these drugs. In the present study, the effectiveness of alternating chemotherapy with the combination regimens I and II was evaluated using 3 lines of cancer xenografts with special emphasis on relapse-free survival. Even in untreated controls, different influences of these cancers on the host as well as differences in their growth rates resulted in delayed tumor death in breast cancer (H-31) compared with pancreas (H-48) and colon (H-110) cancers. Four cycles of the regimen I drug combination failed to prolong life due to toxic side effects in every cancer line. In H-48 cancer, although regimen I alternated with regimen II achieved an inhibition rate (IR) of 96% with tumor shrinkage, 2 of 7 mice died of toxicity. In H-110 cancer, which is only sensitive to VDS, 4 cycles of regimen II alone produced an IR of 83.5%, which was slightly superior to alternating chemotherapy. In H-31 cancer, which retains considerable sensitivity to CDDP, MMC and 5'-DFUR, mice treated with alternating chemotherapy starting from regimen I for a total of 5 cycles attained a maximal IR of over 99% including disappearance of the tumor in 6 of 7 mice during the treatment course, and at the end of the experiment (20th week), all had survived with one in a relapse-free state, compared with the control group which had only 2 survivors. Thus, cyclic delivery of two non-cross-resistant drug combinations with optimal treatment doses and timing prevented toxic effects and induced long-term survival without relapse. Also, this appears to be the first study that has evaluated the effects of cancer chemotherapy in a human solid tumor-nude mouse system according to survival rate.

Animals↗
PubMed1987

[Subrenal capsule assay as a chemosensitivity test (III)--Comparison of host reaction, experimental chemotherapy and use of nude mice].

We studied fundamentally subrenal capsule assay, using human tumor specimens (gastric, breast and pancreas cancers) serially transplanted in nude mice. Any prominent difference of host reaction was not found between the host of BALB/c-nu/+, BALB/c-+/+ and CDF1 mice. Using immunocompetent BALB/c-nu/+ mice, experimental chemotherapy with mitomycin C (MMC) and 5-fluorouracil (5-FU) was carried out. On day 6, macroscopic and histological findings corresponded relatively well with 5-FU effect but not with MMC. Using BALB/c-nu/nu mice, we tried 15-day SRC assay. When the sensitivity of anti-cancer drugs was compared between early and intermediate phase after inoculation, no obvious difference was found macroscopically and histologically. BALB/c-nu/nu mouse will be useful as a host of SRC assay, and could be applicable to clinical fresh cases.

Animals↗
PubMed1987

[Subrenal capsule assay for chemosensitivity test (II)--Sequential changes in the implanted tumor tissue and histological findings].

We carried out fundamental subrenal capsule assay methodology, using tumor specimens of human cancer xenografts (breast cancer and colon cancer) serially transplanted into nude mice. With regard to sequential changes in the tumor grafts implanted under the renal space of immunocompetent mice, tumor size was largest macroscopically around day 6 after inoculation, and later involuted gradually. Histological findings showed that implanted tumor tissues were preserved to a moderate extent until day 4 after inoculation, but leukocyte infiltration by host reaction had begun by day 4, and tumor tissues were almost replaced by host reactive tissues on day 6. Labeling index scoring did not indicate growth of implanted tumor cells. We found that macroscopic tumor size was largest around day 6 because we measured tumor size with involved leukocyte infiltration, and the macroscopic tumor did not represent the true extent of the tumor tissue.

Animals↗
PubMed1986

[Application to chemosensitivity tests of the human tumor-nude mouse system and subrenal capsule assay system].

Since 1974, approximately 200 fresh cancer tissues obtained from various types of cancer patients were inoculated into athymic BALB/c nude mice, of which 30 percent were taken and grown in the subcutaneous space of mice. Among them 15 lines of gastrointestinal and breast cancer xenografts were selected for experimental single agent chemotherapy. The response rates of 14 drugs examined in this xenograft system were compared with the cumulative clinical response rate of each drug in the same type of cancer. Drugs which were clinically effective against one type of tumor were found to be also effective against the corresponding xenograft in nude mice. Thus the human cancer-nude mouse system was considered useful as a predictive secondary screening method for new drugs. This evidence suggested to us the feasibility of utilizing the system as a chemosensitivity test for determining the drugs effective for an individual human malignancy. In our present study, the responses to 15 experimental chemotherapies with single agent or drug combination of 11 lines of cancer xenografts in nude mice were directly compared with the clinical response in each donor patient to the corresponding chemotherapy. Good correlation was obtained between these respective results, the overall predictive accuracy of the experimental results being 93%. Therefore, if the rate of transplantability to nude mice were to be improved, this nude mouse system would become a promising tool for the individual chemosensitivity test. The subrenal capsule (SRC) assay recently introduced by Bogden and his colleagues has excited much attention among Japanese clinical oncologists. In our study, cancer tissues implanted under the renal capsule 6 days after inoculation, did not show marked proliferation and a high percentage of implants was almost replaced by host reactive tissue. It therefore seems necessary to solve some fundamental problems before we can apply this assay method to clinical chemosensitivity trial.

Animals↗
PubMed1986

[Analyses of factors influencing the chemosensitivity of human tumors xenografted into nude mice (I)].

Experimental single-agent chemotherapies using 11 anticancer agents for 15 human cancers xenografted into nude mice revealed that each cancer line seemed to retain a degree of individuality in its spectrum of chemosensitivity irrespective of whether it originated from the same organ or whether it was of a similar histologic type. As possibly factors relevant to this chemosensitivity, we investigated the following 9 parameters in cancer tissue or cancer-bearing mice, i.e., grade of differentiation, vascularity, percentage necrosis, volume doubling time, labeling index (LI), LDH activity, tissue/serum LDH ratio, thymidine phosphorylase activity, and serum CEA. Values of these parameters remained markedly constant within each cancer line. The relationships between these 9 parameters and chemosensitivities to the 11 drugs were investigated in 15 cancer lines. A statistically significant relationship was noted in 22% of the 99 such combinations. Parameters showing a close correlation to chemosensitivity differed from drug to drug, such as ADR vs LI and vascularity, 5'-DFUR vs CEA and vascularity, and MMC vs LDH ratio and grade of differentiation. It was concluded that the chemosensitivity of cancer lines to each drug is a result of various interacting factors.

Animals↗
PubMed1985

[Chemosensitivity of human gastrointestinal and breast cancer xenografts in nude mice].

Experimental chemotherapies for 15 human cancers xenografted into nude mice were performed using 14 anticancer agents including 6 drugs in clinical use. Treatment with each single agent was performed for every cancer line using the maximum tolerated dose through continuous daily (antimetabolites) or intermittent (cytocidal agents) schedules. Effectiveness of each drug was evaluated by inhibition rate (IR) calculated from mean tumor weights of both treated and untreated groups. Response to a treatment was judged as effective when the IR was higher than 58%. Response rate of each drug was as follows; MMC was 67%, UFT 67%, CPA 47%, FT-207 40%, ACNU 33%, ADR 27%, SOAz 87%, 5'-DFUR 80%, MXT 20%, Leakadine 17%, M-83 17%, CAM 0% and GANU 0%. Generally, the experimental results for each drug on the xenografts was in good accordance with the known clinical effect of each drug on the same type of cancer. On the other hand, individual cancer xenografts showed considerable differences in chemosensitivity. Some tumors were sensitive to a majority of the drugs, whereas some were resistant to many of them. Each cancer line seemed to retain individuality in its spectrum of chemosensitivity irrespective of whether it originated from the same organ or whether it was of similar histologic type. This fact suggests the necessity of selecting drugs effective to the individual tumor when considering a patients chemotherapy regime.

Animals↗
PubMed1985

[Microvascular architecture of human gastrointestinal and breast cancer xenografts in nude mice, and its relation to chemosensitivity].

As a tumor factor possibly responsible for chemosensitivity of human cancer xenografts in nude mice, the vascular architecture of tumors growing in mice was investigated in 15 kinds of cancer lines. These consisted of 7 gastric, 3 colorectal, 3 breast and 2 pancreatic cancers. Whole body angiograms of tumor-bearing mice were obtained by perfusing a radiopaque silicone rubber compound (Microfil) through the left ventricle of each mouse. Each cancer retained a characteristic vascular architecture comparable to its histopathological finding. According to the vascularity of the viable part of the tumor, the 15 lines of cancer were classified into 5 groups. Compared with colorectal cancers, stomach cancers had a tendency to decline to a more hypervascular group. There was no apparent relation between vascularity and growth rate, or histological differentiation of the tumors. Among 14 anticancer agents studied, statistically significant correlation between chemosensitivity and vascularity of the 15 cancer lines was observed in 2 drugs, 5'-DFUR and adriamycin. The vascular architecture of the tumors would have some influence in their chemosensitivity through drug accessibility to cancer cells.

Adenocarcinoma↗
PubMed1984

[Effects of 5'-deoxy-5-fluorouridine on human gastrointestinal and breast cancers xenografted to nude mice].

As a preclinical secondary screening trial, the efficacy of a new derivative of 5-fluorouracil, 5'-deoxy-5-fluorouridine (5'-DFUR), on 15 human cancers xenografted serially to nude mice of BALB/c background was evaluated in comparison with two other derivatives, tegafur and UFT. Oral administration of 123 mg/kg/day of 5'-DFUR, 25-30 times, produced effective inhibition in 5 out or 7 gastric cancers, 2 out of 3 colorectal cancers, all 3 of breast cancers and 1 out of 2 pancreatic cancers, totalling 11 out of 15 cancer lines (73%) examined. In some cases shrinkage of tumors was noted without any noticeable side effects. Although an increased dose of 185 mg/kg/day of 5'-DFUR resulted in more prominent inhibition on all 9 tumors tested, some animals suffered from severe loss of body weight or diarrhea. Comparative experiments with of equimolac doses of 5'-DFUR(123 mg/kg) and FT-207(100 mg/kg) showed that the inhibition rate of the former was higher than that of the latter in all 8 lines of cancers examined. Six experiments in particular (2 gastric, 1 colorectal, 2 breast and 1 pancreatic cancers), showed that 5'-DFUR statistically sustained more effective suppression. Direct comparisons of 5'-DFUR and UFT were also made in 5 experiments in which 3 cancers were more sensitive to the former drug. Promising results in clinical trials can be expected with the new drug 5'-DFUR for these kinds of cancers.

Adenocarcinoma↗
PubMed1984

[Experimental chemotherapy of human gastrointestinal and breast cancers in nude mice and its correlation to clinical effect].

For evaluating the predictive value of experimental chemotherapy of human cancers xenografted to nude mice, two types of comparison between experimental responses in nude mouse system and their clinical results were made. The responses of 12 experimental therapies with single agent or drug combination were directly compared with those of the same kinds of therapy in each donor patient. Satisfactory agreement between the two results was shown in every comparison, with 3 true positives and 9 true negatives. Using 15 human cancer lines consisting of 7 gastric, 3 colorectal, 2 pancreatic and 3 breast cancers, single agent treatment with 6 drugs (MMC, ADR, ACNU, FT-207, 5'-DFUR) were performed. The effectiveness of each drug to these xenografts was in good accordance with the known clinical effect of each drug in the same type of cancer. Nude mouse-human cancer panel is useful for the secondary screening of the new drug.

Adenocarcinoma↗
PubMed1984

[Characteristics of lactate dehydrogenase (LDH) isozyme in human cancers transplanted into nude mice and its application to the evaluation of experimental chemotherapy].

Human lactate dehydrogenase (LDH) was universally detected and quantified from sera of nude mice bearing human tumors. The patterns of LDH isozyme in sera reflected exactly those in each tumor extract, and remained unchanged over several generations. In 16 human cancers (7 gastric, 4 colorectal, 2 pancreatic and 3 breast) examined, human LDH levels in serum showed proportional increase as the transplanted tumors grew. Assessment of experimental chemotherapy by measuring the LDH levels of a treated group versus a control group was compared with that obtained by calculating the tumor weight during (14 tests) or after (61 tests) treatments. The percentage inhibition assessed by LDH level was strongly correlated to inhibition rate assessed by tumor weight. Moreover, LDH expressed more rapidly the inhibitory effect of an administered agent than tumor weight. If the drug was effective, serum LDH level in the treated group exhibited a temporary sharp rise within 2 days, thereafter decreasing to a lower level than that of the control. These results imply usefulness in further clinical application.

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