[Cell proliferation kinetics of human gastric, colorectal, pancreatic and breast cancer cell lines serially transplanted in nude mice].
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Biomedical subjects
Publications and source records attributed to K Shimozuma.
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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.
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.
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.
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The Japanese Quality of Life Research Group has developed a general questionnaire suitable for assessing the Quality of Life (QOL) in patients undergoing chemotherapy. The questionnaire covers four major categories: (1) daily activities, (2) physical condition, (3) social activities, and (4) mental and psychological status. The State-Trait Anxiety Inventory (STAI), Self-Rating Depression Scale (SDS), and Performance Status (PS) were used as external measures of quality of life and for the validation of our tool. On the basis of two basic surveys and two studies we selected 22 questions from a larger set of items. Validity and reliability were verified for the final 22-question form. This questionnaire, named the QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD), can be used to detect changes in QOL over time. Its use as an additional outcome measure in Phase III chemotherapy trials should be encouraged.