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PubMed1989

[Clinical application of subrenal capsule assay in ovarian cancer].

The 6-day subrenal capsule assay (SRC) in normal immuno-competent mice was used to test the responsiveness of ovarian cancer to combination chemotherapy and assess the usefulness of SRC in clinical application. A total of 18 different patients in 22 different assays were studied. Twenty-one assays (95%) were evaluable. The predictive sensitivity was 50%, the predictive resistance 75% and the predictive total accuracy 55% respectively. Sensitive drugs in repeated assays in four patients were not changed. Etoposide, cyclophosphamide, cis-platin and adriamycin were sensitive. Etoposide was the most sensitive of four drugs. The response rate was 50% in the patients treated with etoposide as the first line chemotherapy and the second line chemotherapy, respectively. Patients who were treated with sensitive drugs in SRC survived longer than the patients treated with cis-platin combined chemotherapy without etoposide. The median survival time was 19 months and the mean progression free interval was 15 months. In the results of this study, the value of SRC was supported by the results of chemosensitivity tests and etoposide seems useful in chemotherapy in ovarian cancer.

Adult↗
PubMed1990

[Subrenal capsule assay using nude mice].

Six-day subrenal capsule assay (SRCA) using normal immunocompetent mice developed by Bogden et al. is a promising in vivo chemosensitivity test. This method, however, has a problem of influence of the host reaction. We compared the tumor growth kinetics and host reaction between normal immunocompetent and nude mice. The tumor diameter increased until day 6 in normal and day 16 in nude mice, respectively. However the histological finding revealed many host reactive cells and few viable tumor cells on day 6 in normal mice, and well preserved tumour cells on day 16 in nude mice. These results were supported by flow cytometrical analysis. Then, we examined two immunosuppressive drugs; cyclophosphamide (EX) and cyclosporin A (CSA) in SRCA. The tumors increased in the diameter until day 16 in both EX and CSA-treated groups, but the results of the histological examination showed that tumor cells were preserved in tissue on day 14 in CSA-treated and day 6 in EX-treated group. These results were also supported by flow cytometrical analysis. From the investigation of antitumour activities of adriamycin (ADR) and mitomycin C, it was suggested that the 12-day assay was suitable if nude mice were used in SRCA, and six-day assay also, if EX-treated normal mice were used. In CSA-treated group, more toxicity of anticancer drugs was manifested than usual. We studied whether or not CSA had a usefulness in SRCA with normal immunocompetent mice. Sixty mg/kg of CSA was given to BDF1 mice daily SC, and various dosage of ADR was given i.v. on day 2. The body weight of BDF1 mice decreased over 20% within 10 days when ADR was given at more than 5 mg/kg. MX-1, a human breast carcinoma cell line, is known to be sensitive to ADR. This tumor was implanted SC in the back of BALB/c nu/nu mice and chemosensitivity was tested against ADR. ADR resulted to be positive at the dose of 8 mg/kg. On the other hand, the dose of 5 mg/kg proved to be negative, and hence the result of SRCA would be false negative, if the dose of ADR is reduced to avoid the toxicity of CSA. The tumor grew slowly when only 60 mg/kg of CSA was given daily for three weeks, and the inhibition rate was 56.2%. The toxicity of CSA was neglected because the body weight loss was approximately 13%. CSA may have the antitumor effect by itself, and EX did not suppress the host reaction sufficiently.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1989

[Chemosensitivity study using subrenal capsule assay in urinary transitional cell carcinomas].

A subrenal capsule assay (SRCA) was performed on 34 fresh surgical specimens from 31 urinary transitional cell carcinoma (TCC) patients. On day 6, 97.7% of explants were detected macroscopically and tumor cells were present in 45.6% of all explants microscopically. In control groups, there was a negative correlation between the change in explant size (delta TS) and the percentage of the area of interstitial tissue. And in the several explants on day 6, the pseudocysts made up of cancer cells were seen. These support that urinary TCCs from fresh surgical specimens grow under the renal capsule. An evaluable assay rate of 97% was given. Susceptibility to cisplatin (CDDP), adriamycin (ADM), methotrexate and cyclophosphamide (CPM) was seen in 33%, 41%, 32% and 29%, respectively, of tumors using the delta TS method. In interstitial tissue rich tumors, a higher rate of susceptibility to anticancer drugs was given using the delta TS method than using the tumor growth inhibition rate (TGIR) method. There was a positive correlation between the rate of S-phase cells of the tumor and the susceptibility using the delta TS method. But, there was no correlation between this and the susceptibility using the TGIR method. These findings suggest that the delta TS method is more practical than the TGIR method. In addition, the growth of explants was better in immunosuppressed mice with 180 mg/kg of CPM than in normal mice. And the effectiveness of a combination of CDDP and ADM was seen as an anti-tumor effect or a reduction of side effects.

Animals↗
PubMed1987

[Subrenal capsule assay for chemosensitivity testing].

The subrenal capsule (SRC) assay for cancer chemotherapy was tested according to Bogden's methodology. Of 37 patients providing tumor tissue for assay, 29 cases were considered suitable for evaluable assays. Fourteen patients had clinically evaluable diseases and 10 cases were evaluable for SRC assays. Correspondence between sensitive assay and clinical sensitivity was seen in 2 cases, and that between resistant assay and clinical resistance was seen in 4 cases. Discordance between sensitive assay and clinical resistance was seen in 4 cases. In histological studies, cancer tissues implanted in the subrenal space in immunocompetent mice did not show marked proliferation and were replaced by prominent leukocyte infiltration and fibrosis on day 6 after inoculation. The degree of leukocyte infiltration in the xenografts in the mice administered some anti-cancer drugs was slight in comparison with that in untreated control mice, which showed a remarkable trend in xenografts treated with 5-fluorouracil and cyclophosphamide, respectively. Our study suggests that there are many problems involved in the SRC assay methodology of Bogden, and that careful examination of this aspect will be required.

Animals↗
PubMed1984

A four-day subrenal capsule assay for testing the effectiveness of anticancer drugs against human tumors.

The subrenal capsule assay may predict to which anticancer drug a given patient's tumor is sensitive and may also be used to screen new anticancer drugs. The present study documents that the use of this model requires a histological assessment of both the exploitability of a subrenal capsule assay and the extent of drug-induced antitumor lesions. Thirty-five tumors from 34 patients with solid tumor were submitted to a subrenal capsule assay in a total of 1130 male B6D2F1 mice. After being biopsied, each tumor was dissected by a pathologist and cut into 50 pieces (1.5 X 1.5 X 1.5 cu mm), and one piece was implanted under the renal capsule of 35 mice; the mean tumor diameter was measured on Day 0. Mice were randomized into groups of 6 to 10 animals each. On Days 1, 2, and 3, mice were treated either with placebo (control group) or with various anticancer agents. On Days 4 or 6, mice were sacrificed, the mean tumor diameter measured, and the tumor-bearing kidney fixed in Bouin's picroformol solution and processed for histological analysis after staining with hematein -eosin. Seven histological parameters were blindly rated in a semiquantitative fashion yielding a compound score ( PAPAN ) which estimated the overall quality of each xenograft between -3 and +11. On Day 4, as opposed to Day 6, mean lymphocytic infiltration was 3-fold lower (p less than 0.01), and the rate of xenografts containing well-preserved cancer cells was 2-fold larger (p less than 0.01) in three different tumor specimens. Twenty-two of 31 (71%) assays were evaluable, as defined by a histological quality control test. In those, drug effects were demonstrable by statistically significant differences among groups in 2 assays (9%) by using the relative variation in tumor size as an index of drug effectiveness and in 12 assays (54%) by PAPAN histological score. This suggests the higher sensitivity of histological scoring over tumor size measurements. Moreover, no correlation between relative variation in tumor size and PAPAN was demonstrable with statistical significance indicating the poor reliability of tumor size measurements as an index of the antitumor effectiveness of cytostatic drugs.

Adenocarcinoma↗
PubMed1989

[Subrenal capsule assay for chemosensitivity test of urinary tract cancers].

Subrenal capsule assay as a chemosensitivity test was performed on 8 renal cell carcinomas and 7 transitional cell carcinomas using athymic mice. Twelve of the 15 trials were considered suitable for evaluable assay. In 2 of the 3 non-evaluable trials the histological examination showed fibroblasts without cancer cells in the implants of the control group while the implants grew macroscopically. No host cell infiltration was observed microscopically in any implant of the control groups of evaluable assays. Mice were treated with several anticancer agents and sensitivities were evaluated by the tumor growth inhibition rate (TGIR) on the day 10 or 12 and by histological changes. No correspondence was observed between TGIR and histological changes. The characteristic histological finding of the treated groups of transitional cell carcinomas was cystic degeneration and it seemed to be a factor of the discordance between TGIR and the histological changes.

Animals↗
PubMed1989

[Feasibility of subrenal capsule assay as chemosensitivity test for primary esophageal cancer].

Subrenal Capsule Assay (SRCA) as a chemosensitivity test was performed on 39 esophageal squamous cell carcinomas in order to select a more effective chemotherapy and assess the correspondence between the assay results and clinical results. The implant grew progressively for six days and decreased from day 7 in the group of control mice. Histologically, host cell infiltration and new vessel was observed from day 3 after transplantation. Tumor growth curve was not influenced by immunosuppression with cyclophosphamide for six days. As primary esophageal squamous cell carcinomas, two diameter method was more sufficient for evaluating the sensitivity than volume method. Macroscopically, the rate of remained implants was 88.2% and yielded an evaluable assay rate of 94.9%. As to sensitivity, the effective rate of CDDP was 24.3%, BLM was 5.9%, MTX was 8.6% and VDS was 20.7%. Histologically, the rate of tumor cells occupied in implant was decreased by grade of augmentation of effectiveness. Clinically, correspondence between the assay results and clinical result was obtained in 92.3%. SRCA is a new promising chemosensitivity test which is clinically useful, and the present results indicated the feasibility of its use in developing an effective chemotherapy for primary esophageal cancer.

Aged↗
PubMed1989

[Fundamental studies of subrenal capsule assay].

Cancer chemosensitivity test by Bogden's SRCA (subrenal capsule assay) method was experimentally evaluated using DMBA induced rat ovarian cancer. Cancer tissues were implanted beneath the renal capsule of BDF1 mice, and factors affecting development of the xenografts were examined. To observe the effect of the host-mediated immunologic reaction, the mice were put into immunosuppressive situations by applying cyclophosphamide (CPA) or cyclosporin A (CsA), and the growth of the tumor in each condition received macroscopic and histological evaluation. Under the most favorable conditions, drug sensitivity tests were performed. The results obtained were as follows: 1) In non-treated mice, the cancer cells of the grafted tumor were rejected, until the 7th day following the implantation, by host reaction. 2) In a CPA-induced immunosuppressive condition, the tumor tissue was damaged by the cytotoxic effect, although the size of the tumor was on the increase until the 9th day. 3) CsA brought about a favorable condition for tumor development, showing a linear growth curve from the 3rd to the 9th day with viable cancer cells. 4) Chemosensitivity tests indicated that methotrexate and CDDP were effective, while mitomycin was not effective in treating the implanted tumors. 5) The results obtained with SRCA were much the same in experimental therapeutic trials using rats with primary ovarian cancer induced by DMBA application.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

[Responsiveness of gynecological malignancies to oral antitumor agents in subrenal capsule assay and individualization of oral adjuvant chemotherapy].

A subrenal capsule assay (SRCA) was performed to test the sensitivity of 45 gynecological malignancies, including 24 cervical and 15 ovarian carcinomas, to oral antitumor agents, UFT, cyclophosphamide (CPM) and carboquone (CQ). Additionally, using a human endometrial carcinoma (Ishikawa carcinoma), the utility of SRCA in oral adjuvant chemotherapy was also investigated. Thirty-six of 45 cases (80.0%) were found to be evaluable. Regardless of the origin or of the histological type, each gynecological tumor showed a different degree of sensitivity. The results suggested that it is necessary to choose an oral antitumor agent according to the degree of sensitivity in oral adjuvant chemotherapy. In an experimental study with an implanted tumor, 14 of 20 mice (70.0%) developed a recurrent tumor in the control group. Compared to this, the recurrence rates for tumors in mice treated with CPM, CQ and UFT were 10.0% (p less than 0.001), 25.0% (p less than 0.01) and 30.0% (p less than 0.02), respectively. All these agents were considered to be effective in preventing tumors from recurring. In SRCA, the implanted tumor was sensitive to CPM and CQ, but not sensitive to UFT. These data suggested that SRCA is useful in predicting the effect of dose-dependent agents in oral adjuvant chemotherapy, although, with UFT, a time-dependent agent, it is not clear whether SRCA is appropriate for estimating the usefulness of its agent.

Administration, Oral↗
PubMed1990

[Fundamental studies on the subrenal capsule assay as chemosensitivity test for nonsolid tumors].

Fundamental evaluation of the subrenal capsule assay (SRCA) method in nonsolid tumors was made, using two types of murine malignant ascites. Malignant ascites were obtained from mice bearing M-5076 ovarian reticular cell sarcoma or MH-134 hepatoma. These tumor cells were allowed to settle by standing at 4 degrees C to form a jelly-like clot. This clot was cut into fragments about 1mm3 in size and one of these fragments was mashed in trypan blue to estimate the viability grade of the implanted tumor cells. The rest of the fragments were implanted beneath the renal capsule of the mice. On the 6th day after implantation, the assay mice were killed, the increase in the size of the tumor was determined and histological examination was carried out. The results were as follows: (1) The clot was formed reproductively by allowing ascites to settle for one or two days and there was a high viability rate for the tumor cells: 79.9 +/- 11.0% of M-5076 and 90.1 +/- 5.9% of MH-134. (2) The ascites clot thus implanted grew rapidly in the control groups but growth was inhibited by chemotherapy: Tumors were reduced significantly (p less than 0.05-0.005) in the group treated with a single agent. This trend towards a suppressive effect of carcinocidal agents on the tumor growth was more conspicuous as a combination regimen was utilized, a combination of three agents producing the maximum effect. (3) The clot grew more quickly than the solid tumor in both the control and the treated groups. There was a high correlation (r = 0.93 in M-5076, and r = 0.64 in MH-134) between the growth rates of ascites and solid tumor in SRCA. (4) Histological examination revealed that viable tumor cells infiltrated widely under the renal capsule in both types of tumors. These results suggest that ascites and solid tumor are useful materials for the subrenal capsule assay method.

Animals↗
PubMed1990

[Subrenal capsule assay in normal mice immunosuppressed by cyclosporin A].

The subrenal capsule assay in normal mice has more advantages to evaluate sensitivities of anticancer agents than other assays in vivo. However, this method has difficulties because mice reject human tumor grafts by their immune reaction. We examined three methods of immunosuppression in mice; radiation, administration of cyclophosphamide and that of cyclosporin A. The administration of cyclosporin A suppressed host reactions most effectively among the three, and the human tumor grafts in subrenal capsules grew well. We also investigated the intervals of administration and the doses of cyclosporin A in order to evaluate drug response. The minimal dose of cyclosporin A which inhibited host reactions was revealed to be 50mg/kg/day administered subcutaneously to mice. Then the adequate dosage of each anticancer drug for this assay system was investigated so that the body weights of mice do not decrease more than 20%, and the following doses were determined; Mitomycin C: 5mg/kg; Cisplatinum: 4mg/kg; Cyclophosphamide: 100mg/kg and 5FU: 90 mg/kg.

Animals↗
PubMed1988

[Study on the chemosensitivity of liver cell carcinoma by subrenal capsule assay].

Chemosensitivity of liver cell carcinoma was studied by subrenal capsule assay. The method of assay was based on Bogden's one, but the antitumor activity was evaluated by tumor growth inhibition rate (TG-IR). The anticancer agent with more than 50% TG-IR was judged as positive in the chemosensitivity test. Of 3 human hepatoma cell lines transplanted in the subcutaneous space of nude mice, all of 3 were evaluable. The positive rates of ADR, MMC, CDDP, 5-FU and CPA were 66.7%, 100%, 66.7%, 100% and 0%, respectively. Of 24 patients who provided fresh tumor specimens for the assay, 12 (50%) were evaluable. The positive rates of ADR, MMC, CDDP, 5-FU and CPA were 25%, 16.7%, 16.7%, 33.3% and 8.3%, respectively. Our study suggested that 5-FU, MMC and ADR were comparatively active against the hepatoma cell, CDDP was less active than these 3 agents, CPA was inactive. These results seem to justify the use of current anticancer agents against hepatic cell carcinoma and indicate the usefulness of SRC assay for selecting chemotherapeutic agents against liver cell carcinoma.

Animals↗
PubMed1986

Subrenal capsule assay for squamous cell carcinoma of the head and neck.

The murine subrenal capsule assay is an in vivo method for determining the responsiveness of solid tumor xenografts to chemotherapeutic agents. It was used in this study for the purposes of constructing growth curves of squamous cell carcinoma of the head and neck and collecting pilot data on the effects that indomethacin and cisplatin have on this malignant condition. Nine of the ten assays performed were evaluable. Indomethacin, cisplatin, or both were used as treatment drugs in each assay. One-millimeter fragments of viable tumor, from patients with head and neck squamous cell carcinoma, were implanted beneath the renal capsules of normal immunocompetent mice. Baseline and posttreatment measurements were made of the xenografts, and response to treatment was determined by comparing changes in tumor sizes of the test and control groups. Results indicated that reduction in tumor sizes occurred in indomethacin-treated mice in four assays and in cisplatin-treated mice in six assays. In addition, two separate growth curves were calculated by plotting the mean change in tumor size in five mice per day on days 3 through 7. In conclusion, the subrenal capsule assay is a relatively rapid and inexpensive assay in which squamous cell carcinoma remains viable and therapeutic agents can be tested. However, clinical trials that use this assay to choose treatment drugs are needed in order to correlate assay results with clinical responses.

Animals↗
PubMed1987

[A 6-day subrenal capsule assay for predictive testing of primary esophageal cancers].

Subrenal Capsule Assay (SRCA) as a chemosensitivity test was performed on 14 esophageal squamous cell carcinomas in order to select a more effective form of chemotherapy. Of the 14 assays, 12 were evaluable. Mice were treated with anticancer agents (e.g. Cisplatin, Bleomycin, Methotrexate, Vindesine) on days 1 and 3 after transplantation, and on day 6, the sensitivities were determined. Fresh esophageal cancers yielded an evaluable assay rate of 74%. The implant grew progressively for six days in the remaining group of control mice. Histologically, host cell infiltration at the border of the implant was observed from day 3 after transplantation, and cells had degenerated or had been partially replaced by scar tissue by day 6. The results of chemosensitivity tests differed according to the anticancer agent used or from case to case. Clinically, correspondence between the assay results and clinical results was obtained in 5 out of 7 cases. SRCA is a new promising chemosensitivity test which is clinically useful, and the present results indicated the feasibility of its use in developing an effective chemotherapy for esophageal cancer.

Adult↗
PubMed1985

Subrenal capsule assay in choosing cytostatics for gynaecological tumours.

The subrenal capsule assay (SRCA) was used to test the sensitivity of gynaecological tumours to chemotherapy. The total number of the assays was 95, ovarian cancer being the most often tested. Of the SRCAs 92% were evaluable. Of the 59 evaluable assays for ovarian cancer, 52% showed sensitivity, 41% intermediate sensitivity, and 7% resistance to chemotherapy. The previously treated tumours were less sensitive than the untreated ones (p less than 0.01). To the most often tested drug combinations, DOX (doxorubicin) + C (cyclophosphamide) + DDP (cisplatin), DOX + C + Tegafur, and C + V (vincristine), resistance was observed in 10-20% of the assays. However, there was marked interindividual variation. Twenty-five assays of the squamous cell carcinomas were evaluable. Of the tumours 28% were sensitive, 48% intermediately sensitive, and 24% were resistant. Five of 7 sensitive tumours were previously untreated. The combination of DDP and VP-16 (etoposide) was tested most often, followed by Bleo (bleomycin) as a single agent. DDP + VP-16 was significantly superior to Bleo (p less than 0.01). The results of the SRCA and the clinical outcome of the patients could be compared in 31 cases. An overall predictive accuracy rate of 81% was achieved. It was concluded that the SRCA has predictive value in determining chemotherapy responsiveness of gynaecological tumours.

Animals↗
PubMed1990

[Subrenal capsule assay for chemosensitivity test of urological malignancy].

We evaluated the subrenal capsule assay with a chemosensitivity test using 47 fresh surgical explants, including 16 renal cell carcinomas and 10 uroepithelial cancers. Forty-one explants were evaluable and 166 drug tests were performed. Forty-seven tests (28.3%) were found to be sensitive. Ten of 16 renal cell carcinomas involved a sensitive drug, 3 involved more than 2 sensitive drugs. VP-16, ADM, BLM and 5-FU were the most sensitive compared with the others. Concerning the uroepithelial cancers, 8 of 10 involved a sensitive drug, 5 involved more than 2 sensitive drugs. CDDP and VP-16 were more effective than the other drugs. This result showed a good correlation with the clinical therapeutic efficacy using CDDP. In the future, we hope to evaluate the clinical correlation between clinical efficacy and this assay.

Adenocarcinoma↗
PubMed1995

A biochemical evaluation of oral squamous cell carcinoma growth by measurement of specific activity of succinate dehydrogenase in the subrenal capsule assay.

An auxiliary method for determination of chemosensitivity with the subrenal capsule assay (SRCA) was developed in which the specific activity of succinate dehydrogenase (SD) of tumor implanted beneath the renal capsule is measured. The appropriate conditions for measuring the specific activity of SD were determined. The chemosensitivity of tumors, derived from six xenograft lines originating from oral squamous cell carcinomas, to peplomycin (PEP), cisplatin (CDDP), and 5-fluorouracil (5-FU) were evaluated by the SRCA and the nude mouse assay (NMA). The chemosensitivity evaluated by NMA displayed a higher degree of correlation with that determined by the improved SRCA than with that determined by the conventional SRCA. The correlations between overall accuracy of prediction with the NMA and those with the conventional SRCA and the improved SRCA were 72.2% and 88.9%, respectively. These findings suggest that our new assay may be useful for evaluation of chemosensitivity in the SRCA.

Animals↗