Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy.
Flavone acetic acid (FAA), a new drug with broad activity against transplanted solid tumors of mice, induces nonrepairable DNA single strand breaks that correlate with therapeutic efficacy. To test the hypothesis that the inability of the cells to repair single strand breaks is associated with a disruption of tumor energy metabolism, in vivo 31P nuclear magnetic resonance (NMR) spectra were acquired from s.c. implanted Glasgow osteogenic sarcomas in C57BL/6 x DBA/2 F1 mice both before and after treatment with FAA i.v. at 100, 150, or 200 mg/kg and from a control (no treatment) group (n = 4 in each group). While FAA produced a dose-dependent decrease in both the nucleoside triphosphates level and pH, only treatment with an efficacious dose of 200 mg/kg resulted in both a reduction in pH and a complete loss of nucleoside triphosphates from the NMR spectrum at 4 h with no recovery until 48 h and little recovery out to 72 h. The ATP concentration determined by high pressure liquid chromatography in a parallel set of experiments was 5.59 +/- 1.16 (SE) mumol/g (wet weight) in control tumors (n = 9) and 0.24 +/- 0.12 mumol/g (wet weight) at 4 h after 200 mg/kg FAA (n = 7). To examine the possibility that the loss of ATP and decreased pH are associated with a reduction in tumor blood flow, we used 2H NMR to monitor the washout of D2O injected directly into the tumor both before and 4 h after treatment with 200 mg/kg FAA. The pretreatment tumor blood flow of 12.4 +/- 1.7 ml/min/100 g was reduced to 1.9 +/- 0.5 ml/min/100 g at 4 h after treatment (n = 3). The FAA-induced reduction of both tumor blood flow and ATP may play an important role in its mechanism of action and should be considered in the combination of FAA with other drugs or therapeutic modalities. In addition, because 31P NMR can be used clinically, it should provide a nonambiguous early indicator of activity for clinical trials of FAA.
Evelhoch
J L
JL
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201-1998.
Bissery
M C
MC
Chabot
G G
GG
Simpson
N E
NE
McCoy
C L
CL
Heilbrun
L K
LK
Corbett
T H
TH
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003131:Combined Modality Therapy; D005419:Flavonoids / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D010710:Phosphates / Q000032:analysis; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*
D000970:Antineoplastic Agents; D005419:Flavonoids; D010710:Phosphates; C049328:flavone acetic acid; D000255:Adenosine Triphosphate