Mark Edelstein

Comparison between macroscopic and microscopic evaluation of tumour responsiveness using the subrenal capsule assay

Using the subrenal capsule assay in normal mice, a histologic evaluation was made of 8 human primary ovarian tumours and 3 human colon, 2 lung and 5 ovarian carcinomas growing in serial passage in nude mice. The results of the evaluation indicated that there is a tumour- and drug-dependent correlation between the macroscopically and microscopically evaluated effects, with cyclophosphamide demonstrating excellent concordance but adriamycin and cisplatin both demonstrating consistently more tumour cell killing on histologic analysis than could be appreciated macroscopically. Leukocyte infiltration and fibrosis were greatly increased by the latter 2 drugs, leading to unrepresentative macroscopic measurements. Variable amounts of host cell infiltration can also be demonstrated in the untreated control when normal mice are used. The use of nude mice decreases the discrepancy between macroscopic and microscopic evaluation.

Improvements and limitations of the subrenal capsule assay for determining tumour sensitivity to cytostatic drugs

Cyclophosphamide (CY) prevented the host response from occurring in treated animals, and we therefore evaluated CY and other immunosuppressive forms of pretreatment in normal mice using the subrenal capsule assay initially for transplanted and later also for primary tumours. CY pretreatment, 4 or 4.5 Gy whole-body irradiation and cortisone were superior to silica in reducing host cell infiltration, and irradiation as pretreatment has become our routine technique. The addition of cortisone acetate to irradiation was of minor benefit in only 1/3 transplanted lines. When primary tumours were tested, the irradiation was only rarely able to completely prevent cellular infiltration. Only 7/11 ovarian tumours and 3/9 lung tumours were evaluable as tumour specimens (greater than 50% tumour) in preirradiated mice. The degree of infiltration and fibrosis was similar in transplants in irradiated normal mice or in athymic nude mice, suggesting that these phenomena are largely due to properties of the tumours rather than of the host. The limitations of the technique to some cell lines and occasional primary tumours is obvious.

Two types of tumour sensitivity test compared for platinum derivatives.

For early passages of 15 human tumours grown in nude mice two types of test for prediction of sensitivity to cytostatic drugs were carried out for four platinum compounds. The subrenal capsule assay of Bogden was not found to be useful for these early passages, since the response of duplicate tests was not very different from randomly distributed results. The clonogenic assay as described by Hamburger and Salmon gave reproducible results on the drug sensitivity of those tumour cells that grew colonies in vitro. However, in a limited number of cases irregular colony growth occurred. Lower drug concentrations were apparently more effective in killing cells than higher concentrations. From the replicate test results it became clear that such results are not a reliable indicator of drug sensitivity. Furthermore, the critical drug concentrations for optimal testing of drug effectiveness is probably not well represented by a uniform relation to peak plasma level.

The subrenal capsule assay: A critical commentary

Staff Physician, Division of Hematology/Oncology, Veterans Administration Medical Center and Associate Professor, Division of Oncology, Departnwnt of Medicine, Wayne State University, Detroit MI 48202, U.S.A. (A COMMENT ON: Mienpii J, Kangas L, Criinroos M. Predictive testing of vulvar and cervical cancers to chemotherapy by the subrenal capsule assay. Eur J Cancer Clin Oncol 1985, 21, 1141-l 146.)

TUMOR DEPENDENT GROWTH-KINETICS OF HUMAN-TUMOR XENOGRAFTS USING THE SUBRENAL CAPSULE ASSAY

Using the subrenal capsule assay modified by us in order to decrease the ingrowth of host cells, evaluation of the growth kinetics of three human ovarian tumors and one human lung tumor were made by multiple measurements of the tumor implantation site over the 6-day growth period. For all tumors, a lag period of 2-3 days was noticed before growth occurred in the subrenal location. In general, estimation of the composition of the fragments growing under the renal capsule did not change greatly in terms of percentage tumor of which they consisted but by day 6 most had shown a significant degree of host cell infiltration despite the effects of pre-implantation immunosuppression. We would suggest that only certain human tumors are suitable for implantation using this technique. Further, it appears that within even this group of selected tumors only some are suitable for drug studies, those having established exponential growth early enough so that a measurable endpoint can be reached within the 6-day time limit of the assay.

Animal Models for Drug Scheduling

An exhaustive review exclusively concerned with animal systems used to study cytostatic drug scheduling has not appeared earlier. Paragraphs in reviews with a wider scope [1–3] and reviews of NCI contract studies [4] have collected relevant information either on single drug scheduling [4] or on combination therapy [1–3]. A more general review of the validity of animal models has been presented by Carter [5].

In Vitro Screening Model for the Detection of Agents Active Against Myelogenous Leukemia

This study was directed at defining the optimal in vitro screening methodology for the selection of new anti-myelogenous leukemia agents. Using thousands of samples of synthetic compounds from the Eastman Pharmaceutical, Inc. and Sterling Research Corporation (Eastman/Sterling) inventory, a number of sequential combinations of 8 cell lines were employed to optimize the model. The cells in these lines were of either murine (L1210 lymphocytic leukemia, C1498 myelogenous leukemia, and colony-forming unit-granulocyte macrophage [CFU-GM]) or human (HL-60, K-562, HEL, and THP-1 myelogenous leukemias, and CFU-GM) origin. The focus of the study was to find the most efficient and cost-effective manner in which to test compounds for both cytotoxicity against the tumor cells and for differential cytotoxicity against tumor as compared with normal cells.

A phase II study of intravenous 6-thioguanine (NSC-752) in multiple myeloma A Southwest Oncology Group study

SummaryThirty-three patients with relapsing or refractory multiple myeloma were treated with 6-Thioguanine (6TG) at a dose of lg/M2, with therapy given over four hours every three weeks. The major toxicity seen was myelotoxicity; thrombocytopenia was more commonly noted than neutropenia. One patient achieved a PR, two were clinically improved. 6TG in this short infusion schedule proved to be myelotoxic, but demonstrated little activity in previously treated myeloma patients.

Cell Kinetic Factors, Single Drugs and Combination*

This communication focuses on the problems that exist in the application of cell kinetic information in cancer chemotherapy. From selected historical work, the following conclusions can be drawn. 1) Theoretically optimal drug sequences may fail to show the expected effect. 2) Similar drug sequences cause different effects in different tumors, even when the tumors have similar proliferation characteristics. The unpredictability and the heterogeneity in response make the extrapolation to clinical cancer chemotherapy very difficult. Better prediction may be made from the integration of results from studies combining cell kinetic factors, cellular pharmacokinetics, and biochemistry of drug exposure.

Hemorrhagic ascites due to congestive heart failure

Ascites due to congestive heart failure (CHF) is characteristically serous in gross appearance. Although hemorrhage into ascites commonly indicates a malignant or inflammatory cause, cirrhosis of the liver is a well known cause of bloody ascites. We report a case of hemorrhagic ascites due to biventricular congestive heart failure in which workup for other causes was negative and hemorrhage cleared after 4 months. In as much as the mechanism of ascites is similar in both cirrhosis and CHF, we propose that a similar mechanism could cause bleeding into ascites in CHF.