Cell death in cancer and development. AACR special conference in cancer research.
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Apoptosis↗
Biomedical subjects
S Grant
Publications and source records attributed to S Grant.
Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C.
The present studies were undertaken to characterize further the potential role of protein kinase C (PKC) in the regulation of apoptosis in HL-60 promyelocytic leukemia cells. The capacity of acute exposure to specific and nonspecific pharmacological inhibitors of PKC to promote apoptotic DNA fragmentation was examined both quantitatively and qualitatively and correlated with effects on cellular differentiation and proliferation. Incubation of HL-60 cells for 6 h with chelerythrine and calphostin C (highly specific inhibitors that act at the regulatory domain) or H7 and gossypol (nonspecific inhibitors that act at the PKC catalytic domain) produced concentration-dependent increases in DNA fragmentation. Induction of DNA fragmentation by chelerythrine, calphostin C, and gossypol was biphasic, resulting in a sharp decline in effect at concentrations above 5 microM, 0.1 microM, and 100 microM, respectively, whereas maximal and more stable effects were observed in response to H7 (100 microM). A 6-h exposure to staurosporine, a nonspecific but potent PKC inhibitor, failed to induce DNA fragmentation at concentrations generally used to achieve maximal inhibition of enzyme activity (e.g., 50 nM) but promoted fragmentation at considerably higher concentrations (e.g., > or = 200 nM). In contrast, 6-h exposures to the nonspecific protein kinase inhibitor hypericin (0.1 to 100 microM) or to the nonspecific inhibitor of protein kinase A, HA1004 (50 microM), were without effect on DNA fragmentation. DNA obtained from cells exposed to chelerythrine (5 microM), calphostin C (100 nM), H7 (50 microM), gossypol (50 microM), and staurosporine (200 nM)--but not hypericin (25 microM)--exhibited clear evidence of internucleosomal DNA cleavage on agarose gel electrophoresis; moreover, these cells exhibited the classical morphological features of apoptosis (cell shrinkage, nuclear condensation, and the formation of apoptotic bodies). All of the PKC inhibitors that induced apoptosis, and one of the inhibitors that did not (hypericin), substantially inhibited HL-60 cell clonogenicity at the concentrations evaluated. None of the agents tested induced cellular maturation as assessed by nonspecific esterase and nitro-blue tetrazolium positivity. DNA fragments obtained from cells exposed to specific and nonspecific PKC inhibitors possessed predominantly 5'-phosphate termini, consistent with the action of a Ca(2+)-/Mg(2+)-dependent endonuclease. Finally, Northern blot analysis revealed that exposure to calphostin C at a concentration that induced apoptosis (100 nM) failed to alter expression of bcl-2, an oncogene known to block apoptosis in both lymphoid and myeloid leukemia cells.(ABSTRACT TRUNCATED AT 400 WORDS)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Effects of bryostatin 1 and other pharmacological activators of protein kinase C on 1-[beta-D-arabinofuranosyl]cytosine-induced apoptosis in HL-60 human promyelocytic leukemia cells.
We have demonstrated previously that bryostatin 1, a macrocylic lactone with putative protein kinase C (PKC)-activating properties, synergistically augments the antileukemic actions of the deoxycytidine analog 1-[beta-D-arabinofuranosyl]cytosine (ara-C) in HL-60 human promyelocytic leukemia cells (Grant et al., Biochem Pharmacol 42: 853-867, 1991), and that this effect appears to be related to sensitization to ara-C-induced apoptosis (Grant et al., Cancer Res 52: 6270-6278, 1992). In the present studies, we have assessed the extent of this damage by quantitative spectrofluorophotometry of small molecular weight, double-stranded DNA fragments in order to provide: (a) a more complete characterization of the interaction between ara-C and bryostatin 1, and (b) a direct comparison of the relative effects of bryostatin 1 treatment with other pharmacological manipulations known to modulate protein kinase C activity. Exposure of cells to ara-C (10(-9) to 10(-4) M; 1-24 hr) induced time- and concentration-related increases in the extent of DNA fragmentation. Treatment with bryostatin 1 (10(-11) to 10(-7) M; 1-24 hr) alone failed to induce DNA damage, but promoted substantial time- and concentration-related increases in the extent of fragmentation induced by a subsequent 6-hr exposure to ara-C. Maximal potentiation of fragmentation (e.g. 2- to 3-fold greater than that obtained with ara-C alone) was observed following a 24-hr pretreatment with 10(-8) M or 10(-7) M bryostatin 1, and correlated closely with enhanced inhibition of HL-60 cell clonogenicity. The stage-1 tumor-promoter phorbol dibutyrate potentiated the effects of ara-C in a biphasic manner, maximally augmenting the response at 2.5 x 10(-8) M, but exerting no effect at 10(-7) M, whereas the stage-2 tumor-promoter mezerein failed to augment ara-C-related DNA fragmentation at low concentrations, and antagonized ara-C action at high concentrations. In contrast, ara-C-related DNA fragmentation was attenuated or abolished either by continual preexposure to synthetic diglyceride or by pretreatment with exogenous phospholipase C at all concentrations tested. Increased DNA fragmentation was not specifically related to recruitment of cells into S-phase or enhancement of ara-C-related cellular differentiation. Finally, concentrations of bryostatin 1 that maximally potentiated ara-C-related DNA fragmentation were associated with virtually complete down-regulation of total cellular PKC activity, whereas diglyceride and phospholipase C, which suppressed the response to ara-C, moderately increased total PKC activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Antineoplastic Agents↗
The macrocyclic lactone protein kinase C activator, bryostatin 1, either alone, or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor, protects Balb/c and C3H/HeN mice from the lethal in vivo effects of ionizing radiation.
We have examined the in vivo radioprotective effects of the macrocyclic lactone protein kinase C (PK-C) activator, bryostatin 1, administered either alone or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF), in Balb/c and C3H/HeN mice subjected to lethal total body irradiation (TBI). When administered alone on a divided dose schedule (24 hours and 30 minutes before TBI), rmGM-CSF (20 micrograms/kg) was ineffective in increasing survival in either strain. However, in Balb/c mice, bryostatin 1 alone (1 microgram) permitted the long-term survival (60 days) of 70% of the animals following TBI, and 80% when administered in conjunction with rmGM-CSF. Bryostatin 1 administered alone according to this schedule exerted minimal radioprotective effects in C3H/HeN mice, but, when combined with a subeffective dose of rmGM-CSF, allowed 50% of the animals to survive. Treatment of Balb/c mice with bryostatin 1 administered as a single dose 4 hours before TBI resulted in a 20% survival rate, and 45% when administered with rmGM-CSF; corresponding values for the C3H/HeN strain were 60% and 40%, respectively. Lastly, the survival rates of Balb/c mice treated with bryostatin 1 administered as a single dose 4 hours following TBI was 20%, and 25% with rmGM-CSF; corresponding values were 50% and 25% for C3H/HeN mice. These findings indicate that the PK-C activator bryostatin 1 exhibits intrinsic in vivo radioprotective effects in lethally irradiated Balb/c and C3H/HeN mice, and may, under some circumstances, augment the radioprotective capacity of rmGM-CSF. They also underscore the critical role that strain differences and scheduling considerations play in determining the in vivo radioprotective capacity of bryostatin 1, as well as its interactions with rmGM-CSF.
Animals↗
Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway.
The potential involvement of ceramide-related signaling processes in the induction of apoptosis by tumor necrosis factor alpha was assessed by multiple biochemical strategies in the human leukemic cell lines HL-60 and U937 and the murine fibrosarcoma cell lines L929/LM and WEHI 164/13. Exposure of these cells to tumor necrosis factor alpha resulted in internucleosomal cleavage of genomic DNA, yielding laddered patterns of oligonucleosomal fragments characteristic of apoptosis when resolved by agarose gel electrophoresis; similar responses were observed after exposure to exogenous sphingomyelinase or synthetic ceramides. Quantitative spectrofluorophotometry demonstrated that these treatments promoted time- and concentration-dependent degradation of DNA, resulting in the formation of and eventual release of small DNA fragments (< or = 3.0 kb). Corresponding damage to bulk DNA was demonstrated by enhanced-fluorescence alkaline unwinding analysis. DNA fragmentation was not induced by phospholipase C or synthetic diglyceride; in fact, the effects of sphingomyelinase and ceramide were substantially reduced by coexposure to these agents, suggesting opposing roles for diglyceride- and ceramide-mediated signals in the regulation of apoptosis. Phospholipase A2 and arachidonic acid failed to promote DNA fragmentation, as did phospholipase D. Characterization of DNA strand breaks by alkaline and neutral elution analyses confirmed that ceramide action was restricted to breakage of mature, double-stranded DNA but not of nascent DNA. The induction of DNA damage was associated with appearance of apoptotic morphology and decreased clonogenicity. These results demonstrate that the ceramide-dependent signaling system selectively induces apoptosis and raise the possibility that ceramide-activated enzymes represent important components in a signaling cascade involved in the regulation of programmed cell death.
Apoptosis↗
Variable effects of tamoxifen on human hematopoietic progenitor cell growth and sensitivity to doxorubicin.
To determine the influence of tamoxifen on the drug sensitivity of normal human hematopoietic progenitor cells, T-cell- and adherent-cell depleted human bone marrow mononuclear cells (T-, Ad-) were exposed in vitro to 5 microM tamoxifen for 24 h. The effects of tamoxifen were highly variable, as exposure to tamoxifen produced an increase (97% +/- 12.3%) in the growth of day-12 committed myeloid progenitors (CFU-GM) in only four of ten experiments utilizing bone marrow from different donors. When T-, Ad- myeloid progenitor cells treated with tamoxifen were subsequently exposed to doxorubicin, 7 of 14 experimental samples studied demonstrated a net increase in the number of surviving clonogenic cells as compared with cells exposed to doxorubicin alone. Tamoxifen also stimulated the growth of a more purified (CD34(+)-selected) progenitor cell population in four of four experiments (by 62.5% +/- 4.9%) but did not increase the survival of these cells upon exposure to doxorubicin; in fact, in five of ten experimental samples, tamoxifen enhanced cell sensitivity to doxorubicin. Taken together, these observations indicate that tamoxifen produces variable stimulation of committed myeloid progenitor cell growth in vitro. Furthermore, while under some circumstances, tamoxifen appears to have the capacity to enhance CFU-GM survival in the presence of doxorubicin, this drug combination may also result in enhanced toxicity to normal bone marrow progenitors.
Antigens, CD↗
Pregnancy, lactation and the use of silicone breast implants.
In the United States alone, an estimated 1-2 million women have used silicone breast implants. Many of these women are of reproductive age. Given the current controversy over the safety of silicone breast implants, medical care providers should be able to advise women if use of these implants affects the use of any of the available contraceptive methods, whether pregnancy is in any way contraindicated and/or might be associated with special complications, whether there are potential risks to the fetus and neonate, and whether breast feeding might be compromised. A review of the literature on these topics yielded very little useful information.
Breast Implants↗
Breast cancer and silicone breast implants.
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Breast Implants↗
Autoimmune disease following the use of silicone gel-filled breast implants: a review of the clinical literature.
The association between the use of silicone breast implants and the later development of connective tissue disease was reviewed. Data from case reports (only 40 in the world literature), case series, case-control studies, surveys of plastic surgeons, and cohort studies provided no evidence of an association. In many studies, the appropriate information was not collected to evaluate the association. The case-control and cohort studies were too small to detect even moderately increased risks should they exist. Further prospective studies are required to determine the risks of connective tissue disease associated with the use of silicone breast implants.
Adult↗
Cardiorespiratory and symptomatic variables during maximal and submaximal exercise in men with stable effort angina: a comparison of atenolol and celiprolol.
Celiprolol is a novel beta 1 selective adrenoreceptor blocker with partial beta 2 agonism and direct vasodilator activity. These ancillary properties may reduce symptomatic breathlessness and fatigue and modify respiration during exercise. To test this hypothesis 20 men with stable effort angina were enrolled in a double-blind crossover study to investigate the effects of atenolol 100 mg once daily (A) and celiprolol 400 mg once daily (C) on cardiorespiratory and symptomatic variables during maximal and submaximal exercise. Total exercise time on a modified Bruce protocol was similar on both treatments: C12.5 min, A 13.1 min. During steady state submaximal exercise at 60-75% (mean 68%) of maximum work capacity, minute ventilation (C33.81 min-1, A 33.51 min-1), oxygen uptake (C14.6 ml.kg-1.min-1, A15.1 ml.kg-1.min-1), respiratory exchange ratio (C 0.89, A 0.87), ratio of VE/VCO2 (C 33.6, A 33.4), ratio of VE/VO2 (C 2.34, A 2.72), Borg perceived exertion score (C 11.2, A 10.9) and visual analogue scores for breathlessness (C 29.5, A 25.9) and muscle fatigue (C 28.9, A 26.0) were all similar on both treatments. At maximal exercise capacity on the modified Bruce protocol, minute ventilation (C 58.31 min-1, A 60.41 min-1), oxygen uptake (C 21.3 ml.kg-1.min-1, A 21.7 ml.kg-1.min-1), respiratory exchange ratio (C 1.02, A.1.05), ratio VE/VCO2 (C 34.8, A 35.9), and ratio VE/VO2 (C 2.80, A 2.83) were also similar on both drugs. Over a 10 day period anginal attacks (C 10.1 +/- 10.4, A 5.4 +/- 5.9) and sublingual GTN use (C 5.9 +/- 10.3, A 4.4 +/- 9.8) were both more frequent on celiprolol).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Comparison of MADS box gene expression in developing male and female flowers of the dioecious plant white campion.
The MADS box motif is common to genes that regulate the pattern of flower development. To determine whether MADS box genes also play a role in differentiation of the sexes in dioecious plants, we isolated cDNAs (SLM1 to SLM5, for Silene latifolia MADS) with MADS box homology from transcripts of male flower buds of the model dioecious species white campion and compared their expression in developing female and male flowers. SLM1 had extensive sequence similarity to the snapdragon MADS box gene PLENA, SLM2 to GLOBOSA, SLM3 to DEFICIENS, and both SLM4 and SLM5 were similar to SQUAMOSA. Each of the white campion MADS box genes was expressed in the same floral whorls as their respective most homologous snapdragon genes. The sex of the plant affected the pattern of SLM2 and SLM3 expression in the petal and stamen whorls, resulting in a smaller fourth whorl in male flowers than in female flowers. This was correlated with repressed gynoecium development in male flowers. The expression of SLM4 and SLM5 in both sexes differed from that of SQUAMOSA in one important aspect. Unlike SQUAMOSA, they were expressed in inflorescence meristems. This may reflect differences in growth pattern between white campion and snapdragon.
Amino Acid Sequence↗
Risperidone. A review of its pharmacology and therapeutic potential in the treatment of schizophrenia.
Risperidone, a benzisoxazol derivative, is a novel antipsychotic agent which combines potent serotonin (5-hydroxytryptamine) 5-HT2 and dopamine D2 receptor antagonism. Development of the drug was stimulated by reports that the selective serotonin 5-HT2 antagonist ritanserin improved the negative symptoms of schizophrenia and decreased extrapyramidal symptoms when combined with haloperidol. The relatively low incidence of extrapyramidal symptoms with risperidone may reflect a preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways. Recent clinical investigation suggests that risperidone is of at least comparable efficacy to haloperidol and perphenazine in improving the symptoms of acute and chronic schizophrenia on short term administration. Advantages offered by risperidone over haloperidol include a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. If these benefits prove to be maintained during long term therapy, risperidone is likely to make a significant contribution to the treatment of schizophrenia.
Absorption↗
Effects of the protein kinase C stimulant bryostatin 1 on the proliferation and colony formation of irradiated human T-lymphocytes.
The protein kinase C stimulant bryostatin 1 (Bryo) was used in examining human peripheral blood T-lymphocyte radiosensitivities in proliferation assays. Bryo was similar to PMA in inducing T-cell proliferation by the CD3, CD28 and CD69 pathways. No difference in radiosensitivities was observed in T-cells stimulated by the three independent surface antigen-mediated activation pathways. CD3 was chosen as the second signal for comparing the potencies of the three different first signals Bryo, phorbol 12-myristate, 13-acetate (PMA), and interleukin 2 (IL-2) in stimulating T-cell proliferation and in maintaining this response after radiation. Though there were radioresponse differences among various individuals, the irradiated lymphocytes consistently showed significantly greater proliferation when treated with Bryo or PMA than with IL-2 (p < 0.05- < 0.005). No difference in proliferative responses was observed in T-cells irradiated between 4 h before and 15 h after the addition of stimulants. Colony forming assays showed higher colony survival for irradiated T-cells stimulated with Bryo than with PMA. These results support the important role of protein kinase C in T-cell radiation responses, and suggest a potential role for Bryo in enhancing T-lymphocyte survival during radiation therapy.
Adjuvants, Immunologic↗
Induction of differentiation and growth arrest associated with nascent (nonoligosomal) DNA fragmentation and reduced c-myc expression in MCF-7 human breast tumor cells after continuous exposure to a sublethal concentration of doxorubicin.
The effects on DNA integrity of continuous (72-h) exposure of human MCF-7 breast adenocarcinoma cells to 50 nM doxorubicin (a concentration which can be maintained in the plasma by continuous infusion) were characterized by bisbenzimide spectrofluorophotometry, cell flow cytometry, agarose gel electrophoresis, and neutral elution. Spectrofluorophotometry and cell flow cytometry indicated the presence of DNA fragmentation, which was maximal at 24 h. Resolution of these fragments on agarose gels failed to demonstrate "laddered" oligosomal profiles. Neutral elution analysis at 24 h indicated that doxorubicin induced fragmentation of nascent, but not mature, double-stranded DNA. Drug-treated cells exhibited endoreduplication and significant shifts in cell cycle distribution, (i.e., increased G0/G1 and G2/M fractions and a markedly reduced S-phase fraction). These alterations occurred without inhibiting the incorporation of [3H]dThd into cellular DNA; in fact, both the rate and magnitude of [3H]dThd incorporation increased progressively. Doxorubicin also produced a sustained decline in c-myc mRNA levels that paralleled both growth arrest and induction of DNA fragmentation. Ultrastructural examination revealed morphological alterations consistent with the induction of differentiation (e.g., increased lipid content and mitochondrial density, appearance of tight junctions, and secretory ducts) and further suggested the possibility of autocatalysis (e.g., lipofuschin-containing vacuoles). A gradual decline in cell number was observed, with loss of approximately 35% of the cell population after 72 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenocarcinoma↗
Modulation of 1-[beta-D-arabinofuranosyl] cytosine-induced apoptosis in human myeloid leukemia cells by staurosporine and other pharmacological inhibitors of protein kinase C.
We have examined the effects of both nonspecific and highly selective pharmacological inhibitors of protein kinase C (PKC) on the capacity of a 6-h exposure to 1-[beta-D-arabinofuranosyl]cytosine (ara-C; 10 microM) to induce apoptotic DNA fragmentation and cell death in the human myeloid leukemia cell lines HL-60 and U937. Staurosporine, a highly potent, nonspecific inhibitor of PKC (20-50 nM), uniquely potentiated ara-C-related degradation of DNA to oligonucleosomal fragments in both cell lines (i.e., 2- to 3-fold), but was ineffective when given alone at these concentrations. In contrast, co-administration of the nonspecific PKC inhibitor H7 and two highly selective PKC inhibitors, calphostin C and chelerythrine, also increased the extent of DNA fragmentation observed in ara-C-treated cells, but these effects were evident only at inhibitor concentrations that were by themselves sufficient to induce DNA damage. Agarose gel electrophoresis demonstrated that cells co-exposed to staurosporine and ara-C exhibited considerably more pronounced internucleosomal DNA cleavage than did cells exposed to ara-C alone; moreover, this effect was suppressed by Zn2+ (1 mM) and the permeant Ca2+ chelator BAPTA-AM (50 microM). Potentiation of ara-C-related DNA fragmentation by subeffective concentrations of staurosporine was accompanied by a pronounced increase in the morphological features characteristic of apoptosis. A synergistic interaction between staurosporine and ara-C with respect to inhibition of clonogenicity in both HL-60 and U937 cells was demonstrated by median dose-effect analysis. The actions of staurosporine did not result from enhanced ara-C metabolism, as preincubation of cells with concentrations of this agent that potentiated ara-C actions (e.g., 20-50 nM) did not increase intracellular levels of the lethal metabolite ara-CTP. Lastly, preexposure of HL-60 and U937 cells to staurosporine did not block ara-C-mediated upregulation of c-jun, an oncogene whose increased expression has been temporally associated with ara-C-induced apoptosis. Together, these findings indicate that staurosporine exhibits a unique pattern of potentiation of ara-C-related apoptosis in human myeloid leukemias, and provide a rationale for exploring the antileukemic potential of this combination regimen.
Alkaloids↗
Clinical evaluation of Purilens, an ultraviolet light contact lens care system.
Purilens is a new contact lens care system that uses ultraviolet light and subsonic turbulence for lens cleaning and disinfection. In a single hands-off process using only preservative-free sterile saline, the lenses are ready to wear after a 15-minute cycle. This study was designed to test the safety of this contact lens care system. A total of 84 contact lens wearers from six centers were enrolled in the 3-month study, which comprised an initial visit and follow-up visits at 1, 2, 4, 8, and 12 weeks. At the end of the study, lenses and units were collected and a questionnaire was completed. Seventy-six of the 84 subjects (168 eyes) completed the study. No severe eye complications were reported, and no patients were removed from the study because of ocular problems or complications associated with the device or its use. Four patients were removed from the study for noncompliance with follow-up. Another four patients were active for 2 months, but were requested by the sponsor to complete the study 1 month early to complete data collection. Patient satisfaction was high. The study suggests that Purilens may be considered as an alternative for contact lens cleaning and disinfection.
Adolescent↗
High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells.
Mitoxantrone has been shown in vitro to exhibit a steep dose-response relationship with respect to the clonogenic survival of acute myeloid leukemia cells. In this report, we show that 1-hour exposure of human myeloid leukemia HL-60 and KG-1 cells to mitoxantrone concentrations ranging between 0.1 and 10.0 mumol/L induced internucleosomal DNA fragmentation of approximately 200-bp integer multiples, characteristic of cells undergoing programmed cell death (PCD) or apoptosis. Mitoxantrone-mediated PCD was associated with a steep inhibition of the clonogenic survival of the leukemic cells. In addition, intracellularly, mitoxantrone-induced PCD was associated with a marked induction of c-jun and significant repression of c-myc and BCL-2 oncogenes. Pretreatment with the protein kinase C stimulator phorbol myristate acetate enhanced mitoxantrone-induced internucleosomal DNA fragmentation, whereas protein kinase C inhibitors staurosporine and H7 had no effect. These findings suggest that PCD is a potential mechanism underlying the steep dose-response relationship of mitoxantrone to the inhibition of clonogenic survival of acute myeloid leukemia cells.
Apoptosis↗
Modulation by bryostatin 1 of the in vitro radioprotective effects of the GM-CSF/IL-3 fusion protein, PIXY 321, on normal human myeloid progenitors.
We have examined the effect of the macrocyclic lactone PK-C activator, bryostatin 1, on the in vitro radioprotective capacity of the GM-CSF/IL-3 fusion protein, PIXY 321, toward normal committed myeloid progenitors (day 14 CFU-GM). Preincubation of CD 34+ cells for 24 h with 10 ng/ml PIXY 321 exerted significant radioprotective effects on these progenitors, (D = 1.403 vs 0.715 for controls), which were at least as great as those previously reported for higher concentrations (e.g., 50 ng/ml) or rGM-CSF. In contrast to the results of earlier studies involving rGM-CSF, preincubation of cells with both PIXY 321 and 10 nM bryostatin 1 did not lead to an increase in radioprotective effect when the total number of day 14 colonies was assessed. However, combinations of PIXY 321 and bryostatin 1 (or the tumour-promoting PK-C activator, PDBu) significantly increased the relative percentage and absolute number of surviving non-eosinophilic colonies (e.g., pure neutrophil, pure monocyte-macrophage, or mixed neutrophil-macrophage) at each radiation dose level. A similar pattern of response was noted in cells irradiated without a preconditioning interval, and in cells exposed to divided radiation doses. These results indicate that the GM-CSF/IL-3 fusion protein PIXY 321 exhibits significant in vitro radioprotective effects toward normal human bone marrow myeloid progenitors, and that co-administration of PK-C activators such as bryostatin 1 of PDBu selectively augments the radioprotective capacity of this hybrid cytokine toward non-eosinophilic elements.
Bryostatins↗