of circulating IGF-1 and completely block tumor growth.The new antiestrogens, should they become available in the clinic, may facilitate the survival of node-positive patients and be useful to maintain the control of tumor growth in advanced breast cancer.Regrettably, the physiological side-effects that could be associated with the long-term treatment of node negative disease (i.e., atherosclerosis and osteoporosis) may preclude an application in these patients.The concept of a dual ER-mediated control mechanism for regulating breast tumor growth will provide new opportunities to block endocrine-dependent growth completely.The possibility that tamoxifen and other less estrogenic antiestrogens may retard the growth of some ER-negative tumors heralds the broader application of an effective anticancer agent.Indeed, the beneficial therapeutic effect of tamoxifen in patients with a wide range of malignancies (i.e., melanoma, pancreatic carcinoma), cited in numerous anecdotal reports, may be a consequence of reduced serum IGF-1 levels.Pharmacological methods to lower markedly or to eliminate serum IGF-1 levels may prove to be a valuable therapeutic strategy to control a variety of malignancies.Perhaps phase I clinical studies with pure antiestrogens will demonstrate antitumor effects in cancers other than breast cancer via an IGF-1 mediated mechanism.

10.1093/jnci/82.21.1663

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Role of organ-associated NK cells in decreased formation of experimental metastases in lung and liver.

The Journal of Immunology (1985)

Robert H. Wiltrout R B Herberman S R Zhang M. A. Chirigos JR Ortaldo

Mice treated with anti-asialo GM1 (asGM1) serum exhibited increased formation of experimental metastases in lung and liver after i.v. challenge with B16 melanoma or Lewis lung carcinoma. This increased metastasis formation coincided with decreased splenic NK activity and increased survival of i.v. injected radiolabeled tumor cells. In contrast, the injection of mice with the pyran copolymer maleic anhydride divinyl ether (MVE-2) augmented NK activity in the spleen and significantly depressed the formation of experimental metastases in the lungs and liver. However, a single or double administration of anti-asGM1 antiserum to MVE-2-pretreated mice failed to inhibit the immunoprophylaxis associated with MVE-2 administration, although it did decrease splenic NK activity and also increased the survival of i.v.-injected radiolabeled tumor cells. To address the mechanism for this dichotomy, we examined NK activity not only in the spleen but also in the blood, lungs, and livers of MVE-2-treated mice. Levels of NK activity in the lungs and liver were several-fold higher than those observed in spleen and blood. However, MVE-2-augmented NK activity in lung and liver was more resistant to depletion by the standard regimen of anti-asGM1 treatment than was NK activity in blood and spleen, and required two high-dose administrations of a higher titered antiserum for depletion of the augmented response. This high-dose regimen removed all detectable NK activity from the lung and liver, and concomitantly eliminated the metastasis-inhibiting effect of MVE-2. These data are consistent with a role for organ-associated NK cells in inhibiting metastasis formation during the extravasation and/or early postextravasation phases of the metastatic process. The results also suggest that biologic effects of NK activity in spleen and blood can be dissociated from those mediated by NK activity in other organs by use of different treatment regimens with anti-asGM1 serum. Finally, because NK activity in target organs can be augmented to an even greater extent than in the blood and spleen by at least some biologic response modifiers (BRMs), organ-associated NK activity should be considered as a possible mechanism for the therapeutic effects of BRM treatment.

Lewis lung carcinoma

10.4049/jimmunol.134.6.4267

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