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Folate Synthesis Inhibitor

Millar however, has cautioned about possible limitations of combining standard chemotherapy with antiangiogenic therapy or, alternatively, with an oncogene signaling inhibitor that has antiangiogenic activity.Unexpected toxicities may occur, or at the least, lack of increased eff icacy.These patterns of metastatic presentation are well recognized, but their biologic basis has been poorly understood.New experimental evidence suggests that the majority of the presenting patterns of metastases may be dictated by the intensity of angiogenesis in their vascular bed.The essential role that angiogenesis plays in the metastatic cascade can be appreciated by examining animal models that have been developed for each of the common presenting patterns of metastases in cancer patients. Thesefive patterns can be explained by a unifying angiogenic mechanism and will depend mainly upon whether or not a primary tumor generates an angiogenesis inhibitor, which circulate and suppress angiogenesis in remote metastases.Angiogenesis inhibitors might therefore be useful in treating hematologic malignancies.A Piperonyl butoxide recent study reports that the retroviral gene transfer of a vector encoding the direct angiogenesis inhibitors angiostatin and endostatin inhibits bone marrow angiogenesis and tumor growth in a mouse model of leukemia.This therapy was shown to directly inhibit endothelial proliferation in vitro, but to have no effect on leukemia cell proliferation.In the left panel, normal bone marrow shows normal microvasculature of uniform sized vessels.Also, high angiogenesis responders require higher doses of an angiogenesis inhibitor to achieve the same suppression of angiogenesis as a low dose of inhibitor in a low angiogenesis responder.If this early work translates to humans, one can speculate that a low angiogenic host response would decrease the probability of in situ carcinomas switching to the angiogenic phenotype, that tumors that did become angiogenic wouldgrow slowly or be indolent and that relatively low doses of angiogenesis inhibitors would be necessary to achieve effective therapy.In mice, p mutations decrease the response of cancer cells to antiangiogenic therapies.There is currently, however, no quantitative method for determining the total angiogenic output of a patients tumor burden, so L-GLUCOSE surrogate markers such as circulating progenitor endothelial cells are being studied.In fact, the most slowlygrowing tumors are virtually unresponsive to chemotherapy.It has been assumed by some oncologists that slowly growing tumors would be as unresponsive to antiangiogenic therapy as they are to chemotherapy.However, when two types of human bladder cancers, a rapidly growing highly vascularized tumor and a slowly growing poorly vascularized tumor were implanted into immunodef icient mice, growth of both tumor types was inhibited by angiogenesis inhibitors.For a given dose of angiogenesis inhibitor, the slower the tumor was growing, the more effective the inhibitor.In carcinogentreated mice, breast cancers that arose spontaneously andgrew very slowly were inhibited andor regressed by treatment with mouse endostatin.Spontaneously arising carcinomas of the pancreatic beta cells in transgenic mice grew very slowly compared to most transplantable tumors, but retained a high degree of sensitivity to angiogenesis inhibitors.Some cancer patients who have failed conventional therapy lament that their physician told them they were not candidates for antiangiogenic therapy because their tumor was not vascularized.It is sometimes assumed by surgeons that a tumor that appears to be white and avascular is not a candidate for antiangiogenic therapy.

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