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Attempted modulation of disulfide antitumor activity in Balb/c mice through glutathione depletion
R K Coshan-Gauthier1, D L Kirkpatrick
1Department of Chemistry, University of Regina, Canada.
Abstract:
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)
Insights
Buthionine sulfoximine (BSO) depletion of glutathione (GSH) did not enhance the antitumor effects of disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) in mice. However, BSO combined with two doses of compound IV showed significantly increased antitumor activity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Glutathione (GSH) depletion using buthionine sulfoximine (BSO) is a strategy to potentially enhance cancer chemotherapy.
- The antitumor activity of disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) has been investigated.
Purpose of the Study:
- To evaluate the impact of BSO-mediated GSH depletion on the antitumor efficacy of four disulfide derivatives of 6-TG and 6-MP in Balb/c mice.
Main Methods:
- Mice were treated with BSO to deplete tumor GSH levels.
- Disulfide compounds (I-IV) were administered with and without BSO pretreatment.
- Tumor growth delays and growth rates were measured and compared between treatment groups.
Main Results:
- BSO alone did not affect tumor growth.
- Compounds II and III showed no enhanced antitumor activity with BSO.
- Compound I showed modest antitumor effects, not enhanced by BSO.
- Compound IV demonstrated significant antitumor activity, with enhanced efficacy when combined with BSO in a two-dose regimen.
Conclusions:
- BSO-mediated GSH depletion does not universally enhance the antitumor activity of 6-MP and 6-TG disulfide derivatives.
- Compound IV, particularly with a two-dose regimen and BSO pretreatment, shows promising synergistic antitumor effects.