Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.

Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-gamma (IFN-gamma), favours the differentiation of T helper 1 (T(H)1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for T(H)1 responses. Our understanding of the relative roles of IL-12 and other factors in T(H)1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.

Interleukin-12 and the regulation of innate resistance and adaptive immunity

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

The three Es of cancer immunoediting.

Angiogenesis is fundamental to reproduction, development, and repair. All these processes depend on the tightly regulated growth of blood vessels that can “turn on” and “turn off” within a brief period. When blood vessels grow unabated, angiogenesis becomes pathologic and sustains the progression of many neoplastic and non-neoplastic diseases. The realization that tumor growth requires new blood vessels and the identification of chemical factors that mediate angiogenesis have broadened our understanding of pathologic processes and opened new avenues to the diagnosis and treatment of these diseases. Tumor hypervascularity was initially thought to reflect inflammatory vasodilation of preexisting host vessels, a . . .

Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis.

Immune evasion in cancer: Mechanistic basis and therapeutic strategies

Background In previous animal studies, interleukin 12 (IL 12) was shown to inhibit the growth of a wide spectrum of tumors in vivo but to have no direct effect on tumor cells in vitro. Also, contrary to the expectation of a T-cell-mediated effect, the antitumor activity of IL 12 was not completely abrogated in tests of T-cell-deficient mice. These observations suggest that IL 12 may possess antiangiogenic properties that account for its tumor-inhibitory effects in vivo. Purpose Our goal was to investigate the hypothesis that IL 12 has antiangiogenic properties. Methods A model of basic fibroblast growth factor-induced corneal neovascularization in mice was used to evaluate the effects of IL 12 and interferon gamma (IFN gamma) on angiogenesis in vivo. Different strains of male mice, e.g., immunocompetent C57BL/6 mice, severe combined immune-deficient (SCID) mice, natural killer cell-deficient beige mice, and T-cell-deficient nude mice, were treated with IL 12 (1 microgram/day) intraperitoneally for 5 consecutive days. The extent of neovascularization in response to a basic fibroblast growth factor pellet and the inhibition of neovascularization by IL 12 or IFN gamma were assessed by measuring the maximal vessel length and the corneal circumference involved in new blood vessel formation. The antitumor activities of IL 12 and of the angiogenesis inhibitor AGM-1470 were evaluated in Lewis lung carcinoma-bearing mice. In vitro proliferation studies were performed on bovine capillary endothelial cells, mouse pancreatic islet endothelial cells, and mouse hemangioendothelioma cells. Results IL 12 treatment almost completely inhibited corneal neovascularization in C57BL/6, SCID, and beige mice. This potent suppression of angiogenesis was prevented by the administration of IFN gamma-neutralizing antibodies, suggesting that the suppression was mediated through IFN gamma. In addition, the administration of IFN gamma reproduced the antiangiogenic effects observed during treatment with IL 12. Treatment with IL 12 and AGM-1470 combined did not increase toxicity and showed a trend toward enhanced antitumor efficacy in Lewis lung carcinoma-bearing mice. Conclusions IL 12 strongly inhibits neovascularization. This effect is not mediated by a specific cell type of the immune system. Instead, IL 12 has been shown to induce IFN gamma, which, in turn, appears to play a critical role as a mediator of the antiangiogenic effects of IL 12. Implications Recognition of the mechanisms of the antiangiogenic properties of IL 12 may be crucial in planning its clinical applications, including a possibility of coadministration with other inhibitors of neovascularization.

Inhibition of Angiogenesis In Vivo by Interleukin 12

Compounds of the formula ##STR1## wherein R1 is hydrogen or hydroxy and R2 is hydrogen or fluorine are described. The compounds of formula I are useful as agents in the treatment of disease states characterized by metabolic calcium deficiencies. Examplary of such disease states are osteoporosis and renal osteodystrophy.

Vitamin D compounds

The syntheses of 25,26-dehydro-1α,23S-dihydroxycholecalciferol, 25,26-dehydro-1α,23R-dihydroxycholecalciferol, and the epimeric mixture thereof which are useful as differentiation inducing agents and anti-proliferation agents are described, 25,26-dehydro-1α,23S-dihydroxycholecalciferol 25,26-dehydro-1α,23R-dihydroxycholecalciferol and the epimeric mixture thereof are useful for treating tumors and leukemia, and osteoporosis.

25,26-Dehydro-1α,23(S,R)-dihydroxycholecalciferol and its epimers

The syntheses of 25,26-dehydro-1 alpha ,24R-dihydroxycholecalciferol and 25,26-dehydro-1 alpha ,24S-dihydroxycholecalciferol and the epimeric mixture which are useful as differentiation inducing agent and anti-proliferation agents are described. 25,26-dehydro-1 alpha ,24R-dihydroxycholecalciferol, 25,26-dehydro-1 alpha ,24S-dihydroxycholecalciferol, and the epimeric mixture are useful in treating osteoporosis, tumors and leukemia.

25,26-dehydro-1 alpha ,24R-dihydroxycholecalciferol and 25,26-dehydro-1 alpha ,24S-dihydroxycholecalciferol and the epimeric mixture

The compounds 1α,25(S), 26-trihydroxy-Δ22 -cholecalciferol; 1α,25(R), 26-trihydroxy-Δ22 -cholecalciferol; 1α,25(S),26-trihydroxyergocalciferol, 1α,25(R),26-trihydroxyergocalciferol and pharmaceutical compositions comprising the compounds as well as methods of making and using these compounds are disclosed.

Gary Arthur Truitt

Papers

Inhibition of Angiogenesis In Vivo by Interleukin 12

Vitamin D compounds

25,26-Dehydro-1α,23(S,R)-dihydroxycholecalciferol and its epimers

25,26-dehydro-1 alpha ,24R-dihydroxycholecalciferol and 25,26-dehydro-1 alpha ,24S-dihydroxycholecalciferol and the epimeric mixture

Trihydroxy-cholecacliferol and trihydroxy-ergocalciferol for treating leukemia