The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects, yet despite several decades of intensive research work, their exact physiological function remains obscure. Chemically these compounds are organic aliphatic cations with two (putrescine), three (spermidine) or four (spermine) amino or amino groups that are fully protonated at physiological pH values. Early studies showed that the polyamines are closely connected to the proliferation of animal cells. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. Out of these four enzyme, the two decarboxylases represent unique mammalian enzymes with an extremely short half life and dramatic inducibility in response to growth promoting stimuli. The regulation of ornithine decarboxylase, and to some extent also that of adenosylmethionine decarboxylase, is complex, showing features that do not always fit into the generally accepted rules of molecular biology. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur. The biosynthesis of the polyamines thus offers a meaningful target for the treatment of certain hyperproliferative diseases, most notably cancer. Although most experimental cancer models responds strikingly to treatment with polyamine antimetabolites--namely, inhibitors of various polyamine synthesizing enzymes--a real breakthrough in the treatment of human cancer has not yet occurred. It is, however, highly likely that the concept is viable. An especially interesting approach is the chemoprevention of cancer with polyamine antimetabolites, a process that appears to work in many experimental animal models. Meanwhile, the inhibition of polyamine accumulation has shown great promise in the treatment of human parasitic diseases, such as African trypanosomiasis.

Polyamines: from Molecular Biology to Clinical Applications

Publisher Summary This chapter summarizes the third mechanism of oncogene activation—oncogene amplification. It illustrates the various ways by which the oncogenic potential of different proto-oncogenes can be activated. Because of the involvement of myc oncogenes in amplifications in a variety of tumors, other lesions that also activate the cellular oncogene c-myc and the aspects of the normal regulation of this oncogene are also described. Since its discovery in drug-resistant eukaryotic cells, somatic amplification of specific genes has been implicated in an increasing variety of adaptive responses of cells to environmental stresses. Experimental work on drug-resistant cells has shown that in the absence of a selection pressure (drug), double minute chromosomes (DMINs) and the amplified genes that they contain are lost, whereas amplified DNA in the form of homogeneously staining regions (HSRs) is retained in the cells. If DMINs and HSRs contain amplified genes that encode drug-resistant or growth-stimulating protein products, it would follow that the more stable chromosomal form, the HSR, confers a greater selective growth advantage for cells. Although DMINs and HSRs have been described predominantly in tumor cells selected for the resistance to cytotoxic drugs, it is also clear that DMINs and HSRs may be present in cancer cells before the start of therapy.

Oncogene amplification in tumor cells

https://www.kidney-international.org/article/S0085-2538(15)34552-X/pdf

Simulations of peritoneal solute transport during CAPD. Application of two-pore formalism

myc oncogenes: activation and amplification

Genomic Hypomethylation in Human Chronic Lymphocytic Leukemia

Using a mouse cDNA probe for ornithine decarboxylase (ODC), we have identified and isolated an ODC cDNA clone from a λ gt11 recombinant library prepared from human liver cell mRNA. The 2.0-kb insert of this clone hybridizes with several mouse genomic ODC DNA restriction fragments under conditions of low stringency, but reacts with only few human DNA fragments and a polyA+ RNA species of 2.2 kb under both nonstringent and stringent hybridization conditions. This suggests that, unlike the mouse genome, there are only few ODC genes in the human genome. The human ODC DNA fragments segregate with chromosome regions 2pter→p23 and 7cen→qter in mouse × human somatic cell hybrid clones containing normal, translocated, and deleted human chromosomes. Sequences of the short arm of chromosome 2 containing the NMYC oncogene at 2p23→p24 are often involved in DNA amplification in neuroblastomas and small-cell lung cancers. However, in at least three cases—one neuroblastoma cell line, one neuroblastoma tumor, and one lung carcinoma—the ODC sequences are not coamplified with the NMYC oncogene.

Human ornithine decarboxylase sequences map to chromosome regions 2pter----p23 and 7cen----qter but are not coamplified with the NMYC oncogene.

Using Southern blot analysis of panels of human podent somatic cell hybrids and chromosomal in situ hybridization, we have been able to assign human spermidine synthase DNA sequences to lp36 (SRM) and 3p14→q21 (SRML2). Present data suggest that that the former chromosomal site harbors the functional gene and the latter site only a pseudogene.

K.-H. Grzeschik

Papers

Human ornithine decarboxylase sequences map to chromosome regions 2pter----p23 and 7cen----qter but are not coamplified with the NMYC oncogene.

Mapping of the human spermidine synthase gene (SRM) to 1p36 and a probable pseudogene (SRML2) to region 3p14→q21