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Recombinant human stem cell factor (SCF) binds to the c-kit receptor on human bone marrow progenitor cells and enhances their survival following irradiation. Since the c-kit receptor has also been detected on malignant cells, experiments were performed to study the effect of SCF on the proliferation and radiation survival of a variety of both c-kit-positive and -negative human tumor cell lines using [3H]thymidine incorporation and colony formation assays. The addition of SCF to both c-kit-positive and -negative cell line cultures had no significant effect on the stimulation index (in [3H]thymidine assay). In contrast, colony formation by H69 (small cell lung cancer cell line), H128 (small cell lung cancer cell line), and HEL (erythroid leukemia cell line) cells was enhanced by SCF in a dose-dependent manner, but SCF did not promote the in vivo growth of H128 xenograft tumors in terms of graft rate, time from implantation to tumor detection, or tumor size. Furthermore, SCF did not significantly increase the surviving fraction of either c-kit-positive or -negative cell lines following radiation, and there were no statistically significant differences between D0 [defined by the slope of the terminal exponential region of the two-component (single-hit multitarget model) survival curve where slope = 1/D0], Dq (quasithreshold dose), n (extrapolation number), alpha, and beta values for any of the cell lines studied that were irradiated with and without SCF. Finally, nude mice with transplanted human LG425 cutaneous T-cell lymphoma (c-kit positive) were treated with 10 Gy with or without SCF (100 micrograms/kg i.p. 20 h before, 2 h before, and 4 h after irradiation). There were no significant differences in the median tumor quadrupling time between groups that received either no treatment or SCF alone, or between groups treated with 10 Gy and SCF or 10 Gy alone (P > 0.05). These results are encouraging and suggest that SCF does not stimulate tumor cell proliferation in vivo or enhance the survival of tumor cells following irradiation.

Recombinant rat stem cell factor (SCF) has been shown to decrease lethality in mice exposed to total-body irradiation (TBI) in the lower range of lethality through radioprotection of hematopoietic stem cells and acceleration of bone marrow repopulation. This study evaluates the effect of SCF on the survival of the intestinal mucosal stem cell after TBI. This non-hematopoietic stem cell is clinically relevant. Gastrointestinal toxicity is common during and after abdominal and pelvic radiation therapy and limits the radiation dose in these regions. As observed with bone marrow, the administration of SCF to mice prior to TBI enhanced the survival of mouse duodenal crypt stem cells. The maximum enhancement of survival was seen when 100 micrograms/kg of SCF was given intraperitoneally 8 h before irradiation. This regimen increased the survival of duodenal crypt stem cells after 12.0 Gy TBI from 22.5 +/- 0.7 per duodenal cross section for controls to 30.0 +/- 1.7 after treatment with SCF (P = 0.03). The TBI dose producing 50% mortality at 6 days (LD50/6) was increased from 14.9 Gy for control mice to 19.0 Gy for mice treated with SCF (dose modification factor = 1.28). These findings demonstrate that SCF has radioprotective effects on a non-hematopoietic stem cell population and suggest that SCF may be of clinical value in preventing radiation injury to the intestine.

The effect of recombinant human stem cell factor (SCF) on the response of human fetal bone marrow progenitor cells to irradiation was studied using immunodeficient mice with human fetal bone grafts (SCID/Hu mice). SCID/Hu mice were treated with three intraperitoneal injections of 500 micrograms/kg SCF at 20 h before, two h before, and four h after 100 cGy total body irradiation. Fourteen days following irradiation, the fetal bone grafts were harvested and studied. Most of the isolated bone marrow cells were human, as determined by flow cytometry. Colony forming assays were performed on the bone marrow to determine the survival of erythroid (BFU-E) and myeloid (CFU-GM) precursor cells. A statistically significant increase in BFU-E and CFU-GM survival after irradiation was observed for bone marrow maintained in the SCF treated mice when compared to bone marrow from mice not treated with SCF. The enhancement in colony forming unit survival after irradiation ranged from 4.3-fold for BFU-E (p = 0.05) to 13.1-fold for CFU-GM (p = 0.002). These findings suggest that SCF may be of potential clinical value for the prevention of radiation-induced myelosuppression.

This study evaluates the effect of recombinant human stem cell factor (SCF) on the in vitro response of human bone marrow progenitor cells to irradiation. Light density nonadherent mononuclear cells were isolated from human bone marrow and resuspended in either semisolid culture or liquid culture with or without 100 ng/ml SCF. After 24 h in culture, cells were irradiated and assessed for survival of erythroid burst-forming unit, granulocyte colony-forming unit(s), or granulocyte-macrophage colony-forming unit precursors in the presence of erythropoietin, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor, respectively. Incubation with SCF prior to irradiation (0-300 cGy) resulted in an increase in both absolute colony number and surviving fraction for erythroid burst-forming units, granulocyte colony-forming units, and granulocyte-macrophage colony-forming units as compared to cultures that did not contain SCF. The mean surviving fraction enhancement ratio after 100 cGy ranged from 1.2 to 3.7. An increased fraction of CD34+ progenitors in S-phase after exposure to SCF may explain in part the apparent radioprotective effect of SCF on human bone marrow progenitor cells.