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O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.

Clemons M, Kelly J, Watson AJ, Howell A, McElhinney RS, McMurry TB, Margison GP - Br. J. Cancer (2005)

Bottom Line: PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without).In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth.A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK.

ABSTRACT
Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O(6)-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC(50) approximately 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and approximately 60%, with extensive recovery by 24 h. PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P<0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

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Growth of MCF-7 tumour xenografts in nude mice. Treatment was once daily for 5 days. Points are the means (±s.e.m.) of values from at least five mice. See text for experimental details. Tz=temozolomide.
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fig4: Growth of MCF-7 tumour xenografts in nude mice. Treatment was once daily for 5 days. Points are the means (±s.e.m.) of values from at least five mice. See text for experimental details. Tz=temozolomide.

Mentions: The median MCF-7 tqt in the vehicle control and PaTrin-2 only groups were ∼21 and ∼17 days, respectively. Neither temozolomide (tqt∼17 days) nor PaTrin-2 alone had any significant effect on xenograft growth. However, the combination of PaTrin-2 and temozolomide resulted in a median tumour quintupling time of ∼43 days representing an increase of ∼22 days (P<0.005; Figure 4, Table 1). Toxicity, as measured by weight loss, was essentially unaffected by the addition of PaTrin-2 to the temozolomide treatment regimen. At the end of the treatment period, weight loss was ∼5% in both the temozolomide alone and combination groups (Figure 5, Table 1).


O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.

Clemons M, Kelly J, Watson AJ, Howell A, McElhinney RS, McMurry TB, Margison GP - Br. J. Cancer (2005)

Growth of MCF-7 tumour xenografts in nude mice. Treatment was once daily for 5 days. Points are the means (±s.e.m.) of values from at least five mice. See text for experimental details. Tz=temozolomide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361498&req=5

fig4: Growth of MCF-7 tumour xenografts in nude mice. Treatment was once daily for 5 days. Points are the means (±s.e.m.) of values from at least five mice. See text for experimental details. Tz=temozolomide.
Mentions: The median MCF-7 tqt in the vehicle control and PaTrin-2 only groups were ∼21 and ∼17 days, respectively. Neither temozolomide (tqt∼17 days) nor PaTrin-2 alone had any significant effect on xenograft growth. However, the combination of PaTrin-2 and temozolomide resulted in a median tumour quintupling time of ∼43 days representing an increase of ∼22 days (P<0.005; Figure 4, Table 1). Toxicity, as measured by weight loss, was essentially unaffected by the addition of PaTrin-2 to the temozolomide treatment regimen. At the end of the treatment period, weight loss was ∼5% in both the temozolomide alone and combination groups (Figure 5, Table 1).

Bottom Line: PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without).In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth.A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK.

ABSTRACT
Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O(6)-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC(50) approximately 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and approximately 60%, with extensive recovery by 24 h. PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P<0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

Show MeSH
Related in: MedlinePlus