Subrenal Capsule Assay Research Articles

Malignant pericardial effusion in ovarian carcinoma cured by systemic chemotherapy

A case of malignant pericardial effusion in a 67-year-old patient with serous ovarian cystadenocarcinoma is presented. Pericardial effusion was treated successfully with cyclophosphamide, doxorubicin, and cisplatin. The primary tumor had previously been assumed to be sensitive to this combination by using an in vivo predictive test, the subrenal capsule assay.

Sensitivity test for 5-fluorouracil and its analogues, 1-(2-tetrahydrofuryl)-5-fluorouracil, uracil/1-(2-tetrahydrofuryl)-5-fluorouracil (4:1) and 1-hexylcarbamoyl-5-fluorouracil, using the subrenal capsule assay.

The chemosensitivity of 20 human neoplastic tissues including 13 gastric and 7 colorectal cancers was tested using 5-fluorouracil (5-FU) and its analogues: 1-(2-tetrahydrofuryl)-5-FU (FT), uracil/FT (UFT) and 1-hexylcarbamoyl-5-FU (HCFU), and the in vivo subrenal capsule (SRC) assay. The relative variation of tumor size (delta TS/TSo) was calculated as follows: delta TS/TS0 = (TS6-TS0/TS0) x 100%, where TS6 was the tumor size on day 6 and TS0 on day 0, and the chemosensitivity was considered to be sensitive when delta TS/TS0 in the treated group was decreased to below -10%. The mean tumor size was -10.9 +/- (SD) 10.9% for 5-FU, -12.3 +/- 17.1% for FT, -18.4 +/- 15.8% for UFT and -17.9 +/- 15.4% for HCFU. The decrease of tumor size was marked when exposed to UFT (p less than 0.01) or HCFU (p less than 0.02), compared with that to 5-FU. Positive correlations were noted between the tumor sizes of 5-FU and its analogues (5-FU vs. FT, r = 0.851; 5-FU vs. UFT, r = 0.746; 5-FU vs. HCFU, r = 0.685). In 9 tissues resistant to 5-FU, 2 (22%) were sensitive to FT, 4 (44%) to UFT, 5 (56%) to HCFU and 7 tissues (78%) to at least one of these analogues. These results suggest that the SRC assay is useful for predicting the effective drug among 5-FU and 5-FU analogues, for individual patients with cancer.

Combined effects of UFT with other anticancer agents using in vivo chemosensitivity tests.

In order to estimate the combined effects of UFT with other anticancer agents, a nude mouse experimental system (NMES), and a subrenal capsule assay (SRCA) were investigated. Three human tumor xenografts were serially transplanted into nude mice and examined. These were; EH-1 established from esophageal cancer, SH-6 from gastric cancer and CH-3 from colon cancer. The antiproliferative effects were estimated in accordance with the NCI therapeutic protocol. Significant antiproliferative effects were obtained only in NMES and a positive relationship was observed between the two assays (p less than 0.05). In the groups which were treated with a single agent, positive tumor responses were observed against mitomycin C in SH-6, against cis-DD platinum in SH-6 and EH-1, and against adriamycin in EH-1, respectively. On this study the synergistic, additive and subadditive effects were defined as the positive combined effects. The combination of MMC and UFT produced positive combined effects for all xenografts in both assays.

UFT is more antineoplastic against gastric carcinoma than 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil and 1-hexylcarbamoyl-5-fluorouracil.

The sensitivity of human gastric cancer tissue to 5-fluorouracil (5-FU) and its analogues 1-(2-tetrahydrofuryl)-5-fluorouracil (FT), UFT and 1-hexylcarbamoyl-5-fluorouracil (HCFU) was determined, using the in vivo subrenal capsule (SRC) assay. The relative variation of tumor size (delta TS/TS0) was calculated as follows: delta TS/TS0 = (TS6-TS0/TS0) x 100%, where TS6 was the tumor size on day 6 and TS0 on day 0. The chemosensitivity was considered to be positive when delta TS/TS0 in the treated group decreased to below -10%. For their cytotoxic effects, 5-FU analogues are converted to 5-FU and positive correlations were noted between the tumor sizes of 5-FU and its analogues (5-FU vs. FT, r = 0.737; 5-FU vs. UFT, r = 0.653; 5-FU vs. HCFU, r = 0.709), in gastric tissues from 22 patients. The means +/- SD of tumor size were -8.5 +/- 11.5% for 5-FU, -8.3 +/- 16.0% for FT, -18.1 +/- 15.8% for UFT and -13.7 +/- 13.4% for HCFU. Decrease in tumor size was marked in case of exposure to UFT, compared with that to 5-FU (p less than 0.001), FT (p less than 0.001) and HCFU (p less than 0.05). 18% were sensitive to UFT and resistant to 3 other drugs. Thus, UFT proved to be the most effective among 5-FU and its analogues for decreasing the size of gastric cancer tissues.

Anti-tumor activity of recombinant mouse tumor necrosis factor (TNF) on colon cancer in rats is promoted by recombinant rat interferon gamma; toxicity is reduced by indomethacin.

The activity and toxicity of rMuTNF, alone or combined with rat recombinant interferon gamma (rRIFN gamma), was tested in inbred WAG rats bearing a weakly immunogenic colon adenocarcinoma (CC531). The tumor was implanted s.c. or under the renal capsule. A single i.v. injection of 10 micrograms of rMuTNF in non-tumor bearers was lethal in 3 to 5 hr, whereas 2 micrograms was not. Doses of 1 microgram rMuTNF were well tolerated when given daily for one week. The most prominent toxic feature was hemorrhagic colitis which could be alleviated when rMuTNF was preceded by i.p. administration of 10 mg/kg indomethacin. Three intralesional injections of 10 micrograms rMuTNF on days 0, 10 and 15 into s.c. tumors (diameter 1-1.5 cm) led to a moderate retardation of growth in 20% of the cases. Combined with 10(5) units of rRIFN gamma, which on its own had no effect, the overall response rate (arrest of tumor growth or regression) was 50%. Two out of 20 tumors treated intralesionally with rMuTNF and rRIFN gamma regressed. The subrenal capsule assay was used to study the possible interference of indomethacin with the anti-tumor activity of rMuTNF. Tumor cubes of 6-8 mg were implanted under the renal capsule; the test was evaluated by weighing. Treatment with 10 mg indomethacin alone on days 0, 2 and 4 had no effect (40 +/- 8 mg vs. 48 +/- 13 mg in controls) whereas 2 micrograms of rMuTNF on the same days resulted in significant tumor inhibition (24 +/- 7 mg, p less than 0.001). The combined administration of 2 micrograms of rMuTNF and indomethacin had an effect similar to that of rMuTNF alone (25 +/- 9 mg). Under protection of indomethacin the rMuTNF dose was increased from 2 micrograms to 10 micrograms. However, this did not lead to further improvement of the results.

Subrenal capsule assay for fresh human tumors in immunocompetent mice; an inappropriate technique for non-small cell lung cancer

The subrenal capsule assay (SRA) seems to present some difficulties for the evaluation of the chemosensitivity of antineoplastic agents against fresh tumor xenografts. A study was therefore carried out to verify whether two different xenografts would behave in a similar way. Tumors such as melanoma provided adequate homogeneous material for this technique, while non-small cell lung carcinoma (NSCLC) were heterogeneous since the 1 mm 3 specimen grafted under the renal capsule usually contained diffuse areas of necrosis and of infection. Furthermore, a large proportion of the grafted specimens, 257 out of 298, did not contain any tumor at all on microscopic examination even when they showed macroscopic growth. Added to these discrepancies, a random microscopic analysis of 180 adjacent fragments of NSCLC and melanomas demonstrated that the variability of heterogeneous tumors precludes any meaningful comparison between homologous tumor tissues designed to be grafted on treated and on control mice. The anti-inflammatory effect of chemotherapeutic drugs on the host's reaction to the graft is probably responsible for the differences between the macroscopic growth results observed in pieces grafted to both treated and control mice: however, it could not be simulated by hydrocortisone (HC) under our experimental conditions. This allows us to conclude that fresh tumors from NSCLC cannot be used in SRA.

600 - Human Renal Cell Carcinoma in the Six-Day Subrenal Capsule Assay

No AccessJournal of Urology1 Jun 1987Human Renal Cell Carcinoma in the Six-Day Subrenal Capsule Assay Max G. Weissglas, Johannes C. Romijn, Fibo J.W. ten Kate, and Karl H. Kurth Max G. WeissglasMax G. Weissglas More articles by this author , Johannes C. RomijnJohannes C. Romijn More articles by this author , Fibo J.W. ten KateFibo J.W. ten Kate More articles by this author , and Karl H. KurthKarl H. Kurth More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(17)75750-3AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Human Renal Cell Carcinoma in the Six-Day Subrenal Capsule Assay." The Journal of Urology, 137(6), p. 253A © 1987 by The American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 137Issue 6June 1987Page: 253A Advertisement Copyright & Permissions© 1987 by The American Urological Association Education and Research, Inc.MetricsAuthor Information Max G. Weissglas More articles by this author Johannes C. Romijn More articles by this author Fibo J.W. ten Kate More articles by this author Karl H. Kurth More articles by this author Expand All Advertisement PDF downloadLoading ...

Comparative study on nude mice isotope assay (NM-IA) and subrenal capsule assay (SRCA) sensitivity tests of anticancer agents

A comparative study on nude mice isotope assay (NM-IA) and subrenal capsule assay (SRCA) was done to evaluate the usefulness of in vivo assays for predicting individual tumor sensitivity against anticancer agents. Sixty-one fresh tumor specimens collected at surgery, under sterile conditions, were examined. Mitomycin C (MMC), 5-fluorouracil (5-FU), cyclophosphamide (CPM), adriamycin (ADM) and cis-DDPlatinum (CDDP) were used in both assays. In NM-IA, the tumor sensitivity was determined by the amount of 3H-thymidine incorporated into the tumor which had been implanted into subcutaneous spaces of BALB/c nude mice. In the SRCA, the relative increase in weight of the tumor implanted into the subrenal capsular space of ddY mice was determined and measurements made to evaluate the chemosensitivity. Evaluability rates of the trials were 86.9 per cent with both assays and the response rates were 35.8 per cent in NM-IA and 34.0 per cent in SRCA, respectively. Against MMC, 5-FU, CPM, ADM and CDDP, overall consistency rates between the two assays were 77.8 per cent, 88.6 per cent, 72.7 per cent, 81.8 per cent and 68.2 per cent, respectively. In 8 of these 53 evaluated assays, correlations between the results of assays and clinical effects were examined and overall predictive accuracy rates were 87.5 per cent with both assays. Significant differences between these two in vivo chemosensitivity tests were not evident.

Response of ovarian cancer to combined cytotoxic agents in the subrenal capsule assay: Part I

The subrenal capsule assay in normal immunocompetent mice was used to test the responsiveness of ovarian cancer to combination chemotherapy. Of the assays, 42 were of untreated tumors and 19 of previously treated tumors. Fifty-nine (97%) of the assays were evaluable. The previously treated tumors were less sensitive than the untreated ones. Of the treated tumors 44% were sensitive, 33% intermediately sensitive, and 22% resistant versus 56, 44, and 0%, respectively, of the untreated tumors (P less than .01). Repeat assays for the tumors of seven patients were performed successfully after five to eight courses of therapy with the combination of doxorubicin, cyclophosphamide, and cisplatin. The responsiveness to this combination had weakened significantly (P less than .01); the response of only one tumor remained unchanged. The rates of resistance to the drug combinations doxorubicin-cyclophosphamide-cisplatin, doxorubicin-cyclophosphamide-tegafur, and cyclophosphamide-vincristine were 11, 10, and 21%, respectively; there was, however, considerable interindividual variation in tumor responses to these combinations. Of other combinations, hexamethylmelamine combined with 4-epidoxorubicin, aclarubicin, or chlorambucil and cisplatin had effect, whereas the combinations of cisplatin and etoposide and of tegafur and methotrexate or mitomycin were quite ineffective, as measured by the assay. The reliability of the subrenal capsule assay in normal immunocompetent mice is discussed, and it is concluded that the assay can be used to assess the response of ovarian cancer to chemotherapy, including multidrug therapy, without routine histologic control.

Subrenal capsule assay as a predictor of clinical response of ovarian cancer to chemotherapy: Part II

The value of the subrenal capsule assay in predicting the response of advanced ovarian cancer to combination chemotherapy was studied prospectively. The population consisted of 24 patients with advanced or recurrent disease. Using a three-grade interpretation of drug response in the assay (sensitive, intermediately sensitive, and resistant), an over-all predictive accuracy of 79% was achieved. All objective clinical responses and acquired drug resistance could be predicted by the assay. It was concluded that the assay is a promising method for predicting response of patients with ovarian cancer to chemotherapy.

Accurate Prediction of Experimental Cancer Chemosensitivity Using the Subrenal Capsule Xenograft Assay

The chemosensitivity of a murine lung carcinoma grown as a xenograft under the kidney capsule of a rat was compared to the chemosensitivity of this tumor grown as a spontaneous metastasis in its syngeneic host. The chemosensitivity of the tumor to intravenously or subcutaneously administered drugs determined in the short-term xenograft assay accurately predicted the chemosensitivity of this tumor when it was growing as a spontaneous micrometastasis in its syngeneic host, indicating that in both situations the pharmacological determinants of tumor response to anticancer drugs were similar. These results suggest that tumors growing as xenografts under the kidney capsule accurately reflect the responsiveness of these tumors to chemotherapy and support further investigation of the xenograft subrenal capsule assay as a model that may be useful in predicting effective chemotherapy for human tumors.

A comparison of three assays for prediction of clinical response to chemotherapy

AbstractTumors from 30 patients with advanced gynecologic malignancies were evaluated for sensitivity or resistance to various chemotherapeutic agents by three laboratory assays: the subrenal capsule (SRC) assay, the stem cell clonogenic (SCC) assay, and a delayed [3H]TdR incorporation ([3H]TdR) assay. The tumors were tested against a standard battery of chemotherapeutic drugs; 39% of the tumors were sensitive to one or more of these agents in the SRC assay compared to only 24% in the [3H]TdR assay and 4% in the SCC assay. Eighteen of the patients had adequate follow‐up to correlate their clinical course to the assay predictions. In this study, the prospective predictive accuracy (sensitivity) of the SRC assay was 100% compared to 25% for the [3H]TdR assay and 0% for the SCC assay. The respective specificities were 63, 73, and 80%. The SRC assay appeared to predict clinical response for gynecologic malignancies more accurately than either the [3H]TdR or the SCC assay.

Three tumor sensitivity tests evaluated with mouse tumors.

The predictive value of three types of tumor sensitivity tests was evaluated using mouse tumors. Sensitivities of osteosarcoma C22LR, Lewis lung and M2661 carcinoma were determined for the following drugs: DNA interacting or alkylating agent (doxorubicin, cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, melphalan), antimetabolite (5-fluorouracil, methotrexate) and microtubule inhibitor (vinblastine, vincristine). Volume measurements of the subcutaneously growing tumors after treatment with the same drugs were considered to be the traditional reference system with which the results of the in vitro clonogenic assay, the labeled precursor incorporation assay and the subrenal capsule assay were compared. Results obtained with the in vitro clonogenic assay were highly reproducible. With the 1-h drug exposure technique the predictive accuracy was 71%. This result is in the same range as those found by others for human tumors. Predictive accuracy after continuous drug exposure was only 25%. Vinblastine, vincristine and cisplatin caused no inhibition of labeled precursor incorporation. However, the assay is too unreliable to use, due to the extreme variability when used with the other drugs. From 31 consecutively performed duplicate tests in the subrenal capsule assay, nine showed opposite results. This degree of disagreement between duplicate test results was considered too high to make reliable predictions of tumor sensitivity with this assay.

The murine subrenal capsule human tumor implant assay

AbstractThe murine subrenal capsule assay can be used to estimate the susceptibility of fresh human tumor explants to various antineoplastic agents. As a result, the assay has been proposed as a rapid and accurate preclinical laboratory evaluation to determine the sensitivity of human tumors to chemotherapeutic drugs and thereby to assist the direction of cancer patient treatment. The subrenal capsule assay is described in detail and the predictive accuracy of the assay in the clinical setting is discussed.

Subrenal capsule assay applied to examine the sensitivity of allogenic mouse fibrosarcoma to hyperthermia, chemotherapeutic drugs or combined treatment.

The thermosensitivity and chemosensitivity of fibrosarcomas of C3H/He mouse were investigated using the subrenal capsule assay with female ICR mice as host. Five typical chemotherapeutic drugs (mitomycin C, adriamycin, 5-fluorouracil, cis-DDplatinum and cyclophosphamide) tested were effective in suppressing tumour growth. Total-body hyperthermia given at 41.5 degrees C for 30 min twice during the 6-day period exerted little effect. However, an interactive effect was found with the combination of hyperthermia and mitomycin C. The combination of hyperthermia with other drugs failed to exhibit an interactive effect, since the effects of the drugs alone were considerable. The potential clinical applicability of this test is discussed.

Accurate laboratory predictions of the clinical response of patients with advanced ovarian cancer to treatment with cyclophosphamide, doxorubicin, and cisplatin

Seventy-six patients with advanced ovarian cancer treated with Cyclophosphamide, doxorubicin, and cisplatin (CAP) at 3-week intervals were tested for the response of their tumors to treatment with CAP in the subrenal capsule tumor implant assay. Thirty-four of the patients' tumors were assayed prospectively before clinical treatment and 33 were assayed retrospectively, after clinical treatment with CAP. Nine of the patients' tumors were assayed both prospectively and retrospectively. All of the patients underwent a tumor debulking laparotomy. Of the patients with clinically measurable residual disease, 17 had a partial response of at least 50% regression of disease, and 11 had a progression of disease. Of the patients with known residual but nonmeasureable disease, 7 had surgically verified complete responses, 8 at least 50% regression, and 23 had progression of disease: 10 had no evidence of disease clinically but had not had surgical confirmation. Twenty-six of the tumors were adenocarcinomas not otherwise specified (2 grade I, 2 grade II, and 22 grade III), 39 were serous adenocarcinomas (7 grade I, 9 grade II, and 23 grade III), 7 were endometrioid adenocarcinoma (all grade III), 3 were mucinous adenocarcinomas (1 each of grade I, II, and III) and 1 was an adenosquamous carcinoma (grade III). Thirty-four of the patients failed the therapy. The subrenal capsule (SRC) assay predicted 21 of these failures (4 prospective and 17 retrospective). Thirty-two of the patients responded to CAP chemotherapy. The SRC assay accurately predicted the clinical regression of the tumors of 22 of the patients (15 prospective and 7 retrospective). Second-look laparotomy confirmed 7 patients with no evidence of disease, 5 patients with minimal disease, and 5 patients with a greater than 50% reduction of their disease. The SRC assay predicted the response of all these patients except 2 with partial responses to chemotherapy. Thus, while the overall positive predictive value of the SRC assay in this study is 65%, it is 100% for those patients whose tumors respond completely and for those who have minimal residual disease after CAP chemotherapy.

Subrenal capsule assay of fresh human tumors: Problems and pitfalls

The 6 day subrenal capsule (SRC) assay was performed in normal mice using 20 fresh human non-small cell lung cancers and nine fresh ovarian cancers. Different multi-agent chemotherapy regimens administered intravenously on days 2 + 3 of the assay were evaluated for activity against these two tumor types. Macroscopic results measured via an ocular microscope showed high activity for some combinations as well as for single agents. However, when subjected to microscopic examination, the SRC implants in the untreated control animals did not show viable tumor growth on day 6. Detailed histologic evaluation of over 800 SRC grafts reveals an intense inflammatory and fibrotic reaction in the majority of the grafts. These results indicate that drug sensitivity patterns obtained with this assay using only macroscopic criteria do not correlate with actual tumor regression. Microscopic analysis of the grafts prior to transplant shows absence or only minimal presence of tumor in many cases which also contributes to the poor growth observed in these two tumors.

6-day subrenal capsule assay (SRCA) as a predictor of the response of advanced cancers to chemotherapy

The 6- day subrenal capsule assay (SRCA) chemosensitivity prediction test using fresh human tumor xenografts was performed in BALBc mice for 80 advanced cancer bearing patients. Among 97 SRCA, nine were non-evaluable because patients either received no chemotherapy or non-assayed drugs, and 12 were non-interpretable because of inadequate control growth. One hundred and six correlations were established between test results and clinical response, 56 retrospective (chemotherapy then test) and 50 prospective (test then chemotherapy). Among the 56 retrospective correlations there are 45 true negative (−/−) and three false positive (+/−) corresponding to 48 poor clinical responders; and eight true positive (+/+) and 0 false negative (−/+) corresponding to eight good clinical responders. Among the 50 prospective correlations there are 26 true negative (−/−) and four false positive (+/−) corresponding to 30 poor clinical responders; and 19 true positive (+/+) and one false negative (−/+) corresponding to 20 good clinical responders. In total among the 106 correlations there are 98% good negative correlations and 79% good positive correlations. The SRCA is practicable and is available for routine clinical use providing results relevant to cancer site and reflecting previous treatment status.

The 6 day subrenal capsule assay is of no value with primary surgical explants from gastric cancer.

The 6 day subrenal capsule assay is of no value with primary surgical explants from gastric cancer

Accurate prediction of experimental cancer chemosensitivity using the subrenal capsule xenograft assay.

The chemosensitivity of a murine lung carcinoma grown as a xenograft under the kidney capsule of a rat was compared to the chemosensitivity of this tumor grown as a spontaneous metastasis in its syngeneic host. The chemosensitivity of the tumor to intravenously or subcutaneously administered drugs determined in the short-term xenograft assay accurately predicted the chemosensitivity of this tumor when it was growing as a spontaneous micrometastasis in its syngeneic host, indicating that in both situations the pharmacological determinants of tumor response to anticancer drugs were similar. These results suggest that tumors growing as xenografts under the kidney capsule accurately reflect the responsiveness of these tumors to chemotherapy and support further investigation of the xenograft subrenal capsule assay as a model that may be useful in predicting effective chemotherapy for human tumors.