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The synthesis for cis-4,4' (1,2-cyclopropanediyl)bis(2,6-piperazinedione) (cis-3) is discussed. Stereoselective effects on metastases of cis-3 and the previously reported trans-2 isomer were compared to conformationally mobile ICRF-159 using a Syrian hamster lung adenocarcinoma (LG1002). Whereas ICRF-159 and cis-3 significantly inhibited lung metastases the trans-2 isomer significantly increased the number of metastatic nodules in the lung. Thus, these studies have revealed that, at least in one tumor model, antimetastatic activity can be separated from metastatic potentiating activity by controlling drug geometry.

The influence of quantitative differences in dietary linoleic acid (18:2) on the metastasis as well as the development of line 4526 mouse mammary tumors was investigated. High fat diets (20%, w/w) that contained either 1, 2, 4, 8, or 12% 18:2 by weight, were prepared by using mixtures of coconut and safflower oil and fed to female BALB/c mice that were subsequently inoculated with 10(4) 4526 tumor cells s.c., either at the lateral abdominal wall (LAW) or in the mammary fat pad (MFP). Latency of LAW tumors was influenced by the level of dietary 18:2, whereas the latency of MFP tumors was not. When metastasis was assessed, mice with MFP tumors fed 1, 2, 4, or 8% 18:2 diets had 62-73% fewer lung surface tumor nodules than similar mice fed 12% 18:2. Mice in all dietary groups with LAW tumors had fewer metastatic lung nodules than mice with MFP tumors; mice with LAW tumors fed diets containing 1, 2, or 4% 18:2 had 52-69% fewer nodules than similar mice fed diets containing 8 or 12% 18:2. There were no significant differences in the rate of increase of body weight or the daily mean tumor volumes when compared with dietary 18:2 level. Fatty acid composition of the tumor, particularly the level of 18:2, was significantly altered by diet. This study demonstrates that while the level of dietary 18:2 does not enhance the growth rate of primary 4526 tumors and does or does not affect the latency depending on the primary site, it does significantly alter the metastasis. These results stress the importance of metastasis assessment in future studies involving dietary fat effects on tumorigenesis.

Cancer chemotherapy is currently undergoing an intensive reappraisal because of its unimpressive performance against the major common cancers. There are a number of possible reasons for this lack of success; one considered here is that under some circumstances anti-neoplastic drug treatment actually increases the malignant behaviour of tumours. Support for this idea comes mainly from experimental studies in which drug treatments increased metastatic spread. Investigation of this phenomenon shows that drug induced modifications of the host, including immunosuppression and vascular damage, can indeed facilitate metastasis. In addition, new data are presented demonstrating that the direct action of drugs on the tumour cells themselves can have similar enhancing effects. The possible mechanisms underlying such direct effects are discussed and the ability of anti-cancer drugs to cause genetic mutations, amplify genes, and alter gene expression are considered. While the nature and extent of this facilitation of tumour malignancy is not fully understood, it is suggested that this possibility should be considered in the design of treatment protocols.

Experiments were made to investigate the effect of four anesthetic drugs that are commonly used in surgical practice on the postoperative growth of mouse tumors in syngeneic recipients. These experiments revealed that some of the anesthetics when applied for surgical excision of the local tumor, strongly accelerated postoperative progression of spontaneous lung metastases produced by the 3LL Lewis lung carcinoma and by the B16 melanoma. Some of the drugs caused the appearance of metastases in organs, such as the liver, in which spontaneous metastases are not usually produced by these tumors. A T10 sarcoma clone that does not produce detectable metastases in immune intact mice even following intravenous injection, did produce metastases when injected into animals treated with pentothal sodium.

The passage of circulating tumor cells across the vascular wall is an important step in the evolution of cancer metastases. Since tumor cells attach preferentially to subendothelial matrix at sites of endothelial injury and retraction in vitro, we have used an established in vivo model of pulmonary endothelial damage to examine the effects of endothelial injury on the localization and metastasis of circulating tumor cells in vivo. C57BL/6 mice were given a single i.v. dose of bleomycin (120 mg/kg) or multiple i.p. injections (10 mg/kg, twice weekly for 6 wk). Five days after the single injection or 4 days after the last i.p. injection, 2 X 10(5) [131I] iododeoxyuridine-labeled fibrosarcoma cells or unlabeled cells were injected i.v. Two to 8 times as many labeled cells were found in the lungs of bleomycin-treated animals after 24 h. Two and 3 wk after injecting unlabeled fibrosarcoma cells, 1.4 to 5 times more metastatic lung colonies were counted in bleomycin-treated animals than in controls. Morphometric analysis of histological sections demonstrated that the percentage of lung area occupied by tumor in bleomycin-treated animals was between 4 and 16 times that of controls. Analysis of bronchoalveolar lavage fluids demonstrated 5-fold increases of total protein content and leakage of previously injected 125l-labeled albumin, indicating increased endothelial permeability. Electron microscopic examination of lungs of bleomycin-treated mice demonstrated endothelial retraction with exposure of the underlying basement membrane. Electron microscopy of [3H]thymidine-labeled tumor cells, located by autoradiography, demonstrated their attachment to exposed basal lamina. Data from these experiments in vivo support the hypothesis that endothelial damage can facilitate the metastasis of circulating tumor cells.