Effects of glutathione or polyamine depletion on in vivo thermosensitization.
Investigations with the melphalan-sensitive and -resistant human rhabdomyosarcoma xenografts TE-671 and TE-671 MR were performed to examine the effect of glutathione and polyamine modulation on thermosensitivity. Regimens of intraperitoneally injected and orally administered buthionine sulfoximine were utilized to achieve glutathione depletion to 8.7% and 13% of control levels in TE-671 and TE-671 MR, respectively. Animals treated with L-buthionine-S,R-sulfoximine and 42 degrees C or 43 degrees C hyperthermia for 70 min showed no detectable growth delays beyond those observed for hyperthermia alone. Hyperthermia at 42 degrees C of disaggregated TE-671 and TE-671 MR xenografts following growth in short-term culture was performed following preincubation with buthionine sulfoximine or 0.9% saline. Buthionine sulfoximine-mediated glutathione depletion produced a significant increase in hyperthermia-induced cytotoxicity only with TE-671 MR at 43 degrees C. Polyamine depletion was achieved with a 7-day orally administered course of MDL 72.175DA [(2R,5R)-6-heptyne,5-diamine dihydrochloride], an irreversible inhibitor of ornithine decarboxylase. Although this treatment caused significant depletion of intracellular putrescine and spermidine levels, spermine levels remained relatively unaffected. No significant growth delays were observed in either xenograft line for animals treated with MDL 72.175DA or MDL 72.175DA plus hyperthermia as compared with untreated controls. These results contrast with previous work performed in vitro showing synergism between glutathione or polyamine depletion and hyperthermia, and indicate that further studies are needed.
Laskowitz
D T
DT
Department of Pathology, Duke University Medical Center, Durham, NC 27705.
Elion
G B
GB
Dewhirst
M W
MW
Griffith
O W
OW
Casero
R A
RA
Scott
P A
PA
Bullock
N
N
Bigner
D D
DD
Friedman
H S
HS
D000480:Alkynes; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D003131:Combined Modality Therapy; D003959:Diamines / Q000627:therapeutic use; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D014183:Transplantation, Heterologous
D000480:Alkynes; D000970:Antineoplastic Agents; D003959:Diamines; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C039613:6-heptyne-2,5-diamine; D005978:Glutathione