Enhanced uptake of [3H] spermidine by 9L rat brain tumors after direct intratumoral infusion of inhibitors of enzymes of the polyamine biosynthetic pathway.
We have been exploring the feasibility of delivering ionizing radiation to brain tumor cells by using tritium labeled polyamines. Polyamines are taken up preferentially by dividing cells and form noncovalent bonds with DNA. Their uptake can be enhanced by drugs which deplete endogenous polyamines. To test this in vivo, 9L cells were implanted in the striatal region of the brain in male Fisher 344 rats. Osmotic pumps containing trace amounts of [3H] spermidine or [3H] putrescine with either difluoromethylornithine or combinations of 3 inhibitors of enzymes of the polyamine biosynthetic pathway were implanted subcutaneously and were connected to intratumoral cannulas. After 14-16 days the brains were removed and sliced in the coronal plane. The diameters of the tumors were measured and tumor tissue was dissected from each slice, weighed and lysed for scintillation counting. It was found that difluoromethylornithine enhanced the uptake of [3H] putrescine while a combination of inhibitors of enzymes of the polyamine biosynthetic pathway enhanced the uptake of [3H] putrescine and [3H] spermidine producing a localized region of radioactivity in the 9L tumor. It is estimated that if the [3H] polyamines were at higher specific activity (commercially available), instead of the trace dose given here, the [3H] polyamine uptake would be sufficient to kill 9L tumor cells within a 2 to 3 week period.
Redgate
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Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, PA 15261, USA. eredgate+@pitt.edu
Grudziak
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Deutsch
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Boggs
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D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum; D003839:Deoxyadenosines / Q000494:pharmacology*; D000518:Eflornithine / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018316:Gliosarcoma / Q000378:metabolism* / Q000473:pathology; D007263:Infusions, Parenteral; D008297:Male; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D011700:Putrescine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013095:Spermidine / Q000378:metabolism*; D014316:Tritium; D014407:Tumor Cells, Cultured
D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D014316:Tritium; C044445:MDL 72527; C065859:MDL 73811; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine