Enhanced hematopoiesis in sublethally irradiated mice treated with various quinolones.
We compared the effect of 6 quinolones on growth of murine bone marrow (BM) progenitor cells in vitro, and their in vivo effect on repopulation of BM and on survival of sublethally irradiated mice. The addition of clinically attainable concentrations of ciprofloxacin, sparfloxacin or clinafloxacin, in concert with pokeweed mitogen (PWM) to murine spleen cells, resulted in a significant enhancement in colony stimulating activity. A 1.5-1.8 fold increase in the number of myeloid progenitors (CFU-C) was observed in the presence of quinolone-PWM spleen conditioned medium (SCM) (prepared with the above-mentioned quinolones) compared with control cultures exposed to PWM-SCM only. Three other quinolones showed either no stimulatory-effect (fleroxacin, norfloxacin) or had an inhibitory effect (ofloxacin) on CFU-C growth. The stimulatory quinolones share in common a cyclopropyl moiety at position N1 of the quinolone ring. This moiety is lacking in the other 3 quinolones. The secretion of interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by murine spleen cells exposed to quinolone-PWM-SCM was significantly enhanced with all 6 quinolones. However, this effect was associated with a parallel increase in CFU-C only with ciprofloxacin (10 micrograms/mL), sparfloxacin (1 microgram/mL) and clinafloxacin (0.05 microgram/mL). The in vivo activity was assessed in sublethally irradiated mice (650 rad) treated with quinolones for 5 d. The number of CFU-C in BM and the number of peripheral white blood cells (WBC) 8 d post-irradiation was significantly enhanced in mice treated with ciprofloxacin (45 mg/kg/d), sparfloxacin (22.5 mg/kg/d) and clinafloxacin (11.25 mg/kg/d) compared to saline treated animals (p < or = 0.05). Clinafloxacin at higher dosage (45 mg/kg/d) resulted in a decrease in myeloid progenitors in BM. A similar increase in progenitors and WBC was observed in animals treated with high doses, above clinical relevance, of ofloxacin, and norfloxacin (90 mg/kg/d), and with fleroxacin (45 and 90 mg/kg/d). Quinolone-treated animals, at the above-cited doses, showed enhanced survival on d18 compared to saline treated animals. The only exception was the higher mortality of clinafloxacin-treated mice. The above observations imply that certain quinolones, sharing specific molecular structure, are potential immunomodulators at clinically relevant concentrations. These compounds should be further studied in neutropenic patients and BM or peripheral blood progenitor cell recipients.
Shalit
I
I
Infectious Disease Unit, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Kletter
Y
Y
Weiss
K
K
Gruss
T
T
Fabian
I
I
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000528:radiation effects; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000494:pharmacology; D003037:Cobalt Radioisotopes; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned; D016576:Fleroxacin / Q000494:pharmacology; D024841:Fluoroquinolones; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D006454:Hemoglobins / Q000378:metabolism; D007377:Interleukin-3 / Q000096:biosynthesis; D007958:Leukocyte Count / Q000187:drug effects / Q000528:radiation effects; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009643:Norfloxacin / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D014916:Whole-Body Irradiation
D000890:Anti-Infective Agents; D003037:Cobalt Radioisotopes; D017077:Culture Media, Conditioned; D024841:Fluoroquinolones; D006454:Hemoglobins; D007377:Interleukin-3; D015363:Quinolones; D002939:Ciprofloxacin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C057477:clinafloxacin; D015242:Ofloxacin; D009643:Norfloxacin; D016576:Fleroxacin; C061363:sparfloxacin