Buthionine sulfoximine pretreatment potentiates the effect of isolated lung perfusion with doxorubicin.
BACKGROUND
Although surgical resection remains the mainstay of treatment for metastatic pulmonary sarcoma, 5-year survival approaches only 25%. Chemotherapy has been limited by tumor resistance and systemic toxicity. We assessed the efficacy of L-buthionine-SR-sulfoximine, an inhibitor of glutathione synthesis, as a sensitizer for isolated lung perfusion.


METHODS
In experiment 1, sarcoma-bearing rats (n = 20) received either buthionine sulfoximine via intraperitoneal injection or Hespan. After the last injection, tumor glutathione levels were measured. In experiment 2, rats (n = 60) were injected with sarcoma intravenously. On day 6, animals were pretreated with either buthionine sulfoximine or Hespan intraperitoneally. On day 7, rats underwent isolated lung perfusion (Hespan or doxorubicin) or intravenous therapy (Hespan or doxorubicin). On day 14, tumor nodules were counted.


RESULTS
Buthionine sulfoximine effectively depleted tumor glutathione. Animals treated with intravenous therapy had no response to therapy, whereas those animals treated with doxorubicin isolated lung perfusion alone had a limited response. Buthionine-sulfoximine pretreatment in combination with doxorubicin isolated lung perfusion led to a 13-fold reduction in tumor nodules and 5 complete responses.


CONCLUSIONS
Buthionine-sulfoximine pretreatment in combination with doxorubicin isolated lung perfusion is superior to intravenous doxorubicin and doxorubicin isolated lung perfusion alone for the treatment of metastatic pulmonary sarcoma.
Port
J L
JL
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Hochwald
S N
SN
Wang
H Y
HY
Burt
M E
ME
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D010478:Chemotherapy, Cancer, Regional Perfusion; D004317:Doxorubicin / Q000627:therapeutic use*; D004357:Drug Synergism; D005978:Glutathione / Q000032:analysis; D006895:Hydroxyethyl Starch Derivatives; D008099:Liver / Q000737:chemistry; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000737:chemistry / Q000188:drug therapy* / Q000556:secondary
D000964:Antimetabolites, Antineoplastic; D006895:Hydroxyethyl Starch Derivatives; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D005978:Glutathione