Paper
A biochemical mechanism for the delayed cytotoxic reaction of 6-mercaptopurine.
Published Apr 1, 1974 · D. Tidd, A. Paterson
Cancer research
310
Citations
7
Influential Citations
Abstract
6-Thioguanosine-35S and β-2′-deoxythioguanosine-35S were identified in venom hydrolysates of RNA and DNA isolated from 6-mercaptopurine (MP)-35S-treated L5178Y cell cultures. Digestion with purified phosphodiesterases demonstrated that MP is incorporated as thioguanine (TG) nucleosides in 3′,5′-phosphodiester linkages in DNA and RNA. 3′-Nucleotides of TG-35S were released from 35S-labeled DNA and RNA by digestion with micrococcal nuclease plus spleen phosphodiesterase. The 5′-ribonucleotide of TG-35S was released from 35S-labeled RNA by digestion with venom phosphodiesterase, and the 5′-deoxyribonucleotide of TG-35S was released from 35S-labeled DNA by digestion with pancreatic deoxyribonuclease plus venom phosphodiesterase. A relationship between delayed cytotoxicity and incorporation of MP as TG into nucleic acids was apparent in the following observations. Mycophenolic acid protected L5178Y cells against the delayed cytotoxic effect of MP and suppressed MP incorporation into nucleic acids. A spontaneous development of partial tolerance to MP in two lines of L5178Y cells was associated with a reduced capacity for incorporation of MP as TG into DNA and RNA. 6-Methylthioinosine potentiated cytotoxic effects of MP in a partially tolerant cell line and stimulated incorporation of MP into DNA and RNA. Nucleic acid-incorporated TG was the major thiopurine derivative in MP-sensitive cells at the time of the delayed cytotoxic reaction to MP exposure. Pulse exposure of cells to equitoxic concentrations of MP-35S and TG-35S resulted in similar levels of incorporation of TG-35S in nucleic acids. The delayed cytotoxic activity of MP is probably a consequence of MP anabolism to TG nucleotides followed by incorporation of the latter into DNA. It is likely that the same biochemical mechanism is responsible for delayed cytotoxic effects of both MP and TG.
In Vitro Study
Highly CitedThe delayed cytotoxic effect of 6-mercaptopurine is likely due to its anabolism to thioguanine nucleotides and their incorporation into DNA, potentially affecting both MP and TG effects.
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