Attempted modulation of disulfide antitumor activity in Balb/c mice through glutathione depletion.
We investigated the effects of buthionine sulfoximine (BSO)-mediated glutathione (GSH) depletion on the antitumor activity in Balb/c mice produced by four disulfide derivatives of 6-TG and 6-MP. Initial studies indicated that 14 h after BSO (5 mmol/kg) injections, tumor GSH levels were maximally depleted, while normal tissue GSH levels had returned to near control levels. Tumor growth delays and growth rates were compared for groups of animals receiving disulfides I-IV with and without BSO administration 14 h previous. Treatments with BSO alone produced no delay or growth rate differences from the control. Compounds II or III administered in the presence and absence of BSO also produced no delay or growth rate differences from control. Compound I (10 mg/kg) alone showed a delay of 5.2 days and a growth rate significantly slower than that of control (p = 0.05). In combination with BSO the effects were not enhanced. Compound IV (50 mg/kg) also produced delays in 2 separate trials (3.1 and 4.8 days) and significantly slower growth rates on each occasion compared to the control (p = 0.05). The growth rates were not significantly lowered in the presence of BSO. Administration of two doses of IV, 4 days apart, produced a delay (4.9 days) similar to that seen with a single dose. It produced 2 cures and was also more toxic, causing 3 deaths. Two doses of IV in combination with BSO pretreatment had a greater delay (16.0 days) and a significantly longer growth rate (p = 0.05) than two doses of IV alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Coshan-Gauthier
R K
RK
Department of Chemistry, University of Regina, Canada.
Kirkpatrick
D L
DL
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D005978:Glutathione / Q000378:metabolism*; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000378:metabolism; D013329:Structure-Activity Relationship; D013866:Thioguanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000963:Antimetabolites; D000970:Antineoplastic Agents; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D015122:Mercaptopurine; D013866:Thioguanine; D005978:Glutathione