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Low doses of granulocyte- colony stimulating factor (G-CSF) and granulocyte macrophage- colony stimulating factor (GM-CSF) have been shown to be beneficial in reducing duration of systemic antibiotic therapy and in-patient hospitalization by decreasing the period of neutropenia in cancer patients undergoing chemotherapy. Since the underlying mechanism is unclear, the aim of this study was to investigate whether the administration of G-CSF and GM-CSF in two different doses (low dose and standard dose) would result into resolution of neutropenia with concomitant increase in multiple forms of dihydrofolate reductase (DHFR, a pivotal enzyme in the pathway of de novo DNA synthesis). Thirty seven cancer patients (26 males and 11 females; age 14-73 years) having chemotherapy-induced neutropenia (absolute neutrophil counts <500/μl) were treated with colony stimulating factor (CSF) in the following manner: 11 received GM-CSF (7 received a dose 250 μg/m2 and 4 received a dose of 100 μg/m(2)); 26 received G-CSF (14 received a dose of 5 μg/kg and 12 received a dose of 2.5 μg/kg). CSFs was given every day till the absolute neutrophil count was more than 1,000/μl. Ten ml blood was collected from each patient and analyzed for total leukocyte count (TLC) and active DHFR and immunoreactive nonfunctional form of DHFR (IRE) in the cytoplasm of blood leukocytes by using methotrexate binding assay and enzyme-linked immunosorbent assay (ELISA). A significant increase (p<0.05) in concentrations of both active DHFR and IRE following stimulation with low as well as standard doses of CSFs was observed along with increase in the TLC. There was no significant difference in number of days to resolution of neutropenia at these two doses, indicating that even low doses of CSFs are clinically effective. Along with an increase in TLC, the levels of DHFR increased even at low doses of CSF suggesting that this might be one of the mechanisms for CSF-induced proliferation of leukocytes in neutropenic cancer patients.