Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

7.5.1
Sources of Polyamines
Polyamines are found in all in all living cells. Polyamine levels (urine, serum and
red blood cell) have been correlated with stage of malignancy and tumor burden
[262, 263]. In addition, because dying tumor cells release high levels of polyamines,
circulating polyamine levels have been proposed to serve as indicators of the success
of chemotherapeutic agents [264±266]. In addition, food is a significant exogenous
source of polyamines [267].
Polyamine biosynthesis can be selectively blocked by d,l-2-(difluoromethyl)ornithine
(DFMO). DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC) which
mediates the first step in polyamine synthesis [268]. DFMO depletes the cells of intracellular
putrescine and spermidine (but not spermine), and inhibits cell proliferation
without cell death [269]. DFMO treatment is associated with weight loss and
toxicity, and therefore led to the development of less toxic polyamine analogs. Polyamine
analogs such as N 1 ,N 8 -bis(ethyl)spermidine [270] are reported to rapidly deplete
intracellular polyamines and induce cell death. Because exogenous polyamines
found in food also contribute to the polyamine status of an individual, blockade of
endogenous and exogenous (polyamine-deficient diet) is sometimes required to identify
the role of polyamines on host immunosuppression during tumor growth [267].
Inhibitors of polyamine biosynthesis have been shown to inhibit tumor growth and
metastases in vivo [271±276]. Interestingly, these inhibitors prevent the growth and
metastases in experimental models of B16 melanoma and Lewis lung carcinoma
when the tumor cells are s.c. implanted, but not when tumor cells are i.v. injected
[273]. Much of the antitumor activity of ODC inhibitors has been attributed to their
antiproliferative activity [277±281]. However, polyamines also appear to play a role in
the differentiation of tumor cells [282], protease expression [283], invasiveness [284],
protection against apoptosis [285, 286], malignant transformation [284, 287±290] and
tumor-associated angiogenesis [291, 292]. Inhibitors of polyamines biosynthesis prevents
proliferation of normal and tumor cells in vitro, including small cell lung carcinoma
[278], mammary tumor cells [281] and melanoma cells [282]. However, tumor
cells may be more dependent on polyamines for proliferation than normal host cells
due to their increased proliferative rate (reviewed in [293]). In addition to their numerous
effects on tumor cells, polyamines serve as suppressors of the host immune
system.
7.5.2
Effects of Polyamines
7.5 Polyamines
7.5.2.1 Effects of polyamines on monocytes/macrophages
Polyamines are associated with numerous functional activities of macrophages/monocytes
that may contribute to host immunosuppression during tumor growth. Inhibitors of polyamines
biosynthesis inhibit TNF-a-mediated macrophage activation [294], and the
respiratory burst of macrophages [295], whereas polyamines block both NO [296,
297] and cytokine synthesis [298] by macrophages. In addition, a negative correlation
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