© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 9, 805-806,
May 5, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Macrophage Role in the Anti-Prostate Cancer Response to One Class of Antiangiogenic Agents
Affiliations of authors: I. B. J. K. Joseph (The Johns Hopkins Oncology Center), J. T. Isaacs (The Johns Hopkins Oncology Center, Department of Urology), The Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: John T. Isaacs, Ph.D., The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, 422 N. Bond St., Baltimore, MD 21231.
We thank Dabrowska and colleagues for their efforts in demonstrating
that the combination of interleukin 12 (IL-12) with Linomide®
potentiated the antiangiogenic and antitumor effects of each
monotherapy in a murine melanoma model. IL-12 released by activated
macrophages is an inducer of interferon gamma (IFN-
) and
indirectly of interferon IFN--inducible protein (IP-10), which
inhibits angiogenesis. IP-10 and Linomide inhibit different steps in
the angiogenic process. IP-10 inhibits the differentiation of
endothelial cells into tube-like structures but does not affect
endothelial cell proliferation, migration, or invasion (1). On
the other hand, Linomide inhibits endothelial cell proliferation,
migration, and invasion (2). In addition, IL-12 inhibits tumor
cell production of vascular endothelial growth factor (VEGF) through
IFN- while Linomide does not inhibit VEGF production by tumor
cells (3,4). Thus, Linomide and IL-12 appear to have
different, but complementary, mechanisms of action, which results in
potentiated antitumor effects when they are combined.
It is interesting to note that the authors administered Linomide intraperitonially at a dose of 400 mg/kg. We have demonstrated better antiangiogenic and antitumor effects in our human prostate cancer xenograft models when Linomide was administered orally at a much lower dose (5). This observation indicates that the oral route of administration is more effective than the parental route for mice. The authors could have achieved optimal antitumor effects had they administered Linomide in drinking water.
It is also interesting to note that, when Linomide or IL-10 monotherapy was terminated on day 21 after tumor inoculation, the subsequent tumor growth was enhanced. In contrast, in the combination group, the subsequent rate of tumor growth was not enhanced following termination of treatments. We also have observed similar effects with Linomide in our rodent prostate cancer models, suggesting that Linomide needs to be administered at least intermittently (6).
EDITOR'S NOTE
Larry M. Wahl and Hynda K. Kleinman declined to respond to Anna Dabrowska et al.'s correspondence.
REFERENCES
1
Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM,
Maheshwari S, et al. Human intereron-inducible protein 10 is a potent inhibitor of angiogenesis
in vivo. J Exp Med 1995;182:155-62.
2
Vukanovic J, Passaniti A, Hirata T, Traystman RJ, Hartley-Asp
B, Isaacs JT. Anatiangiogenic effects of the quinoline-3-carboxamide Linomide. Cancer
Res 1993;53:1883-7.
3 Dias S, Boyd R, Balkwill F. IL-12 regulates VEGF and MMPs in a murine breast cancer model. Int J Cancer 1998;78:361-5.[CrossRef][Web of Science][Medline]cancerlit;98437962
4
Joseph IB, Isaacs JT. Potentiation of the antiangiogenic ability of
Linomide by androgen ablation involves down-regulation of vascular endothelial growth factor in
human androgen-responsive prostatic cancers. Cancer Res 1997;57:1054-7.
5
Vukanovic J, Isaacs JT. Human prostatic cancer cells are
sensitive to programmed (apoptotic) death induced by the antiangiogenic agent Linomide. Cancer Res 1995;55:3517-20.
6 Hartley-Asp B, Vukanovic J, Joseph IB, Strandgarden K, Polacek J, Isaacs JT. Anti-angiogenic treatment with linomide as adjuvant to surgical castration in experimental prostate cancer. J Urol 1997;158:902-7.[CrossRef][Web of Science][Medline]cancerlit;97402738
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