The multiple systemic administration of multilamellar liposomes composed of phosphatidylserine and phosphatidylcholine (molar ratio 3:7) that contained water-soluble muramyl dipeptide (MDP) activated alveolar macrophages to become tumoricidal and eradicated established spontaneous pulmonary and lymph node metastases. Spontaneously metastasizing melanoma cells were injected into the footpads of mice. After 4-5 weeks, the tumors were resected by a midfemoral amputation; 3 days later, twice-weekly injections of liposomes were initiated and continued for 4 weeks. In some experiments the mice were killed 2 weeks after the final treatment. Seventy-four Percent of animals injected with liposomes containing MDP were free of visible metastases. In a separate life-span experiment, 60% of mice treated with liposome-encapsulated MDP were tumor-free 120 days after the last liposome treatment or 110 days after all control mice treated with free MDP or control liposome preparations had died of disseminated cancer. These data suggest that the systemic administration of liposomes containing MDP, or similar compounds that produce macrophage activation, may provide an additional useful approach to the therapeutic regimens currently used to eradicate cancer metastases.Metastasis of malignant neoplasms is responsible for most therapeutic failures in clinical oncology (1-3). Recent studies suggested that metastases can result from the proliferation of a minor subpopulation of cells within the primary tumor and that tumors can be heterogeneous with regard to many phenotypic characteristics such as drug sensititivity and metastatic potential (1-3). Such biological diversity among metastases implies that successful therapy of disseminated disease must include a regimen that acts by a mechanism independent of this heterogeneity.One biological agent that appears to function against tumor cells without regard to their phenotypic diversity is the activated macrophage. At least in vitro, macrophages can distinguish tumorigenic from nontumorigenic cells by a mechanism that is independent of such phenotypic characteristics as drug sensitivity, metastatic potential, and antigenicity (4). Moreover, to date, attempts to select in vitro tumor cells resistant to macrophage-mediated cytotoxicity have been unsuccessful (5).The increasing evidence that macrophages are important in host defense against neoplasia has stimulated interest in agents that can enhance macrophage-mediated destruction of tumor cells. Normal macrophages can be activated to become tumoricidal by various agents such as lymphokines and by whole microorganisms or their products such as endotoxins (6). However, the use of whole viable microorganisms or their products to activate macrophages in vivo has been hampered by a number of undesirable side effects (7).The search for synthetic compounds that are relatively nontoxic yet possess immune potentiating activities has resulted in the demonstration that N-acetylmuramyl-L-alanyl-D-isoglutamine [muramyl dipeptide. (MDP), Mr 49...

rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.

Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.

Treatment with rhEndostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors.

ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC 50 values ranging from 0.025 to 0.7 mmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinumresistant ovarian cancer.

Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position 17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198, ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with hep-

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