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Effects of trimethoprim on leukaemic cells in vitro
Abstract:
Trimethoprim-Sulfamethoxazole (TMP-SMZ) is a fixed combination of antibiotics which is widely used for prophylaxis and treatment of infections in patients undergoing cancer chemotherapy. TMP has been reported to inhibit growth of haemopoietic stem cells in vitro. If TMP-SMZ inhibits leukaemic cell growth, it could interfere with antileukaemic treatment, especially with S phase specific agents. TMP-SMZ at a concentration of 10 micrograms/ml (TMP) produced 50% inhibition of incorporation of 3H-deoxyuridine in DNA of L1210 and human lymphoblastic leukaemia cell. TMP-SMZ (1 g/ml TMP) produced 30% prolongation of doubling time of L1210 in vitro. Pure TMP (10 micrograms/ml) but not SMZ (50 micrograms/ml) produced the same effect as TMP-SMZ. Cell inhibitory effects could be completely reversed by folinic acid. These findings suggest that TMP produces some degree of inhibition of dihydrofolic acid reductase in mammalian cells and can potentially influence the effects of chemotherapy on tumour and/or host cells.
Insights
Trimethoprim-Sulfamethoxazole (TMP-SMZ) may inhibit leukaemia cell growth by affecting DNA synthesis. This antibiotic
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Trimethoprim-Sulfamethoxazole (TMP-SMZ) is a common antibiotic for cancer patients.
- TMP may inhibit hematopoietic stem cell growth.
- Potential interference of TMP-SMZ with chemotherapy, particularly S-phase specific agents, is a concern.
Purpose of the Study:
- To investigate the in vitro effects of TMP-SMZ on leukaemic cell growth.
- To determine if TMP-SMZ interferes with DNA synthesis in leukaemic cells.
- To explore the mechanism of TMP-SMZ's potential anti-leukaemic activity.
Main Methods:
- Assessing DNA synthesis inhibition via 3H-deoxyuridine incorporation in L1210 and human lymphoblastic leukaemia cells.
- Measuring the effect of TMP-SMZ on leukaemic cell doubling time in vitro.
- Evaluating the impact of pure TMP and SMZ separately on leukaemic cells.
- Investigating the reversibility of observed effects with folinic acid.
Main Results:
- TMP-SMZ (10 micrograms/ml TMP) inhibited DNA synthesis by 50% in leukaemic cells.
- TMP-SMZ (1 microgram/ml TMP) increased leukaemic cell doubling time by 30%.
- Pure TMP, but not SMZ, mimicked the inhibitory effects of TMP-SMZ.
- Folinic acid completely reversed the cell inhibitory effects.
Conclusions:
- TMP exhibits dihydrofolic acid reductase inhibitory activity in mammalian cells.
- TMP-SMZ's potential to inhibit leukaemic cell growth warrants consideration in cancer chemotherapy.
- The findings suggest TMP-SMZ could influence the efficacy of certain anti-leukaemic treatments.