Use of phosphorous-31 nuclear magnetic resonance spectroscopy to determinesafe timing of chemotherapy after hepatic resection

Liver resection induces accelerated growth of residual hepatic micrometasta ses, Adjuvant chemotherapy may improve outcome if administered early after resection but may prove lethal if initiated prior to completion of DNA synt hesis in regenerating liver. This study investigates phosphorus-31 nuclear magnetic resonance (P-31-NMR) as a noninvasive tool for measuring energy ch anges reflective of hepatic DNA synthesis and for predicting safe timing of chemotherapy after 70% hepatectomy. To evaluate metabolic changes in regen erating liver, quantitative three-dimensional P-31-NMR was performed, using the technique of chemical shift imaging at various time points after 70% h epatectomy in adult male Fischer rats. Animals receiving a course of 2'-deo xy-5-fluorouridine (FUDR; 100 mg/kg, i.p. four times per day x 5), initiate d at the time of operation, were also evaluated to observe the effects of c hemotherapy on li, cr regeneration. Forty-eight hours after resection, hepa tic nucleoside triphosphate (NTP), which reflects ATP content, fell 37% (P < 0.03) in animals undergoing hepatectomy alone, By contrast, animals recei ving FUDR after hepatectomy demonstrated a mitigated NTP response, with a d rop of only 17% (P = not significant), suggesting that interruption of DNA synthesis leads to a reduced consumption of ATP, Direct measures of DNA syn thesis and nuclear proliferation were correlated with NMR findings. [H-3]Th ymidine incorporation and Ki67 immunohistochemistry were performed on liver samples from rats undergoing 70% hepatectomy with and without FUDR, Both [ H-3]thymidine incorporation and Ki67 expression were inhibited significantl y at 48 h in animals receiving hepatectomy and FUDR, compared with those no t treated with FUDR, To determine whether NMR changes could be used to iden tify safe timing of chemotherapy after hepatectomy, rats mere treated with a 5-day course of FUDR initiated either prior to or after NMR changes norma lized, Animals treated with FUDR at the point of NTP normalization (72 h) s howed significantly improved survival over those that began treatment at op eration (75% versus 17%; P = 0.0005, log rank test). FUDR inhibits hepatic DNA synthesis and influences mortality if administered too early after hepa tectomy. Chemical shift imaging is a noninvasive tool that can identify met abolic changes coinciding with DNA synthesis and nuclear proliferation afte r hepatectomy, P-31-NMR may be useful for determining safe timing of chemot herapy after liver resection.