Polyamines in Mammalian Tumors Part ii

Scalabrino, Giuseppe; Ferioli, Maria Elena

doi:10.1016/s0065-230x(08)60422-4

Cited by 114 publications

(53 citation statements)

References 272 publications

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“…ODC activity which is transiently increased upon growth factor exposure becomes constitutively activated during cell transformation (Gilmour et al, 1987). Elevated levels of ODC are frequently detected in transformed cell lines (Scalabrino and Ferioli, 1982), animal tumors (Scalabrino and Ferioli, 1981), and in some pre-neoplastic lesions (Luk and Baylin, 1984). In addition, induction of ODC activity and polyamine biosynthesis is critical in experimental animal models of carcinogenesis (O'Brien, 1976).…”

Section: Signal Transduction Studiesmentioning

confidence: 99%

Cooperativity between the polyamine pathway and HER-2neu in transformation of human mammary epithelial cells in culture: Role of the MAPK pathway

et al. 1998

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Section: Signal Transduction Studiesmentioning

confidence: 99%

Cooperativity between the polyamine pathway and HER-2neu in transformation of human mammary epithelial cells in culture: Role of the MAPK pathway

et al. 1998

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“…They are involved in numerous steps of protein synthesis, affect the biological activity of proteins, stabilize nucleic acids, and contribute to cell growth (1). For these reasons, the need for polyamines in tumor cells is crucial, and high levels of polyamines have been detected in many tumor types (2,3). Such an accumulation might be a good marker for defining patients with high risk of progression, as shown with colon cancer (4) or renal cell carcinoma (5).…”

Section: Introductionmentioning

confidence: 99%

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

Barret¹,

Kruczynski²,

Vispé³

et al. 2008

Cancer Research

139

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The polyamine transport system (PTS) is an energy-dependent machinery frequently overactivated in cancer cells with a high demand for polyamines. We have exploited the PTS to selectively deliver a polyamine-containing drug to cancer cells. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a watersoluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS. F14512 is 73-fold more cytotoxic to Chinese hamster ovary cells compared with CHO-MG cells with a reduced PTS activity. A decreased sensitivity of L1210 leukemia cells to F14512 was observed in the presence of putrescine, spermidine, and spermine. In parallel, the spermine moiety considerably enhances the drug-DNA interaction, leading to a reinforced inhibition of topoisomerase II. The spermine tail of F14512 serves as a cell delivery vehicle as well as a DNA anchor, and this property translates at the cellular level into a distinct pharmacologic profile. Twentynine human solid or hematologic cell lines were used to characterize the high cytotoxic potential of F14512 (median IC 50 of 0.18 Mmol/L). Finally, the potent antitumor activity of F14512 in vivo was evidenced with a MX1 human breast tumor xenograft model, with partial and complete tumor regressions. This work supports the clinical development of F14512 as a novel targeted cytotoxic drug and sheds light on the concept of selective delivery of drugs to tumor cells expressing the PTS. [Cancer Res 2008;68(23):9845-53]

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“…Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels (Haddox et al, 1980;Scalabrino et al, 1982;Holtta et al, 1988;Holtta et al, 1993), which is mediated by increased polyamine biosynthesis and enhanced uptake of polyamines. ODC is the ®rst and rate limiting enzyme in the pathway that leads to the formation of polyamines from ornithine (Davis et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation

et al. 1999

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Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels, which is mediated by increased polyamine biosynthesis and enhanced uptake of polyamines. Polyamine biosynthesis is catalyzed particularly, in the level of ornithine decarboxylase (ODC). The elevation of cellular polyamine levels on the other hand accelerates the induction of ornithine decarboxylase antizyme (antizyme), which is involved not only in ODC-degradation, but in the negative regulation of polyamine transport. Taking advantage of these characteristics of antizyme, the potential of antizyme as a factor having anti-cell growth and anti-tumor activity was investigated. We show that antizyme can induce cell death associated with a rapid decline of intracellular polyamine contents. The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 12)-transformed NIH3T3 cells and several human malignant cell lines including a line with loss of p53 expression, and they were shown to be as sensitive as nontransformed NIH3T3 cells in vitro. The in vivo antitumor activity was also tested using nude mice inoculated with H-ras transformed NIH3T3 cells that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice. These results suggest that ectopic antizyme expression is of possible therapeutic bene®t in the treatment of cancer, which is mediated by ODC inactivation and intracellular polyamine depletion.

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Polyamines in Mammalian Tumors Part ii

Cited by 114 publications

References 272 publications

Cooperativity between the polyamine pathway and HER-2neu in transformation of human mammary epithelial cells in culture: Role of the MAPK pathway

Cooperativity between the polyamine pathway and HER-2neu in transformation of human mammary epithelial cells in culture: Role of the MAPK pathway

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation

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