| الوصف: |
Polyamines are biologically important molecules in DNA and RNA function, transcription and protein synthesis, and appear to be necessary for the propagation and invasion of cancer cells, viability of parasites and, possibly, progression of neurodegenerative diseases. Ornithine decarboxylase (ODC) is a rate-limiting enzyme of polyamine biosynthesis, catalyzing the conversion of ornithine to putrescine. From here, specific synthases anabolize putrescine to spermidine and thence to spermine utilizing aminopropyl groups donated by decarboxylated S-adenosylmethionine (dcAdoMet) after conversion of S-adenosylmethionine (AdoMet) by S-adenosylmethionine decarboxylase (AdoMetDC). Together, ODC and AdoMetDC are two critical enzymes supplying the cellular polyamine pool. For these reasons, drugs that inhibit these two enzymes would be expected to have anticancer activity and an ability to inhibit survival of parasites and possibly prevent or at least delay the progression of neurodegenerative diseases. In this chapter, we discuss, in some depth, the results of anticancer trials with α-difluromethylornithine (DFMO, eflornithine, ornidyl), methylglyoxal bis(guanylhydrazone) (mitoguazone, MGBG, methyl-GAG) and SAM486A (CGP48664, free base of 4-(aminoimino-methyl)-2,3-dihydro-1H-inden-1-one-diaminomethylenehydrazone). These drugs have been shown to have variable efficacy to control leukemia and solid tumor growth. DFMO is currently evaluated in combination with etoposide in pediatric patients with neuroblastoma. In addition, DFMO has been used in colon-cancer polyp chemoprevention trials with success. DFMO has been approved for the treatment of Trypansoma brucei infection, but no polyamine synthesis inhibitor has been approved for the treatment of cancer, although DFMO and MGBG have shown good clinical activity in clinical cancer trials. In addition, polyamine inhibitors may also become of interest for the treatment of human neurodegenerative diseases, but to date, no clinical trials have been performed. |
