In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients

Bronchud, Miguel H.; Potter, M; Morgenstern, G. R.; Blasco, M. J.; Scarffe, J. H.; Thatcher, Nick; Crowther, Derek; Souza, Lawrence M.; Alton, N. K.; Testa, Nydia G

doi:10.1038/bjc.1988.163

Cited by 179 publications

(64 citation statements)

References 21 publications

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“…The potential for nephrotoxicity from the high kidney dose and the potential cross-fire effects from kidney to marrow are currently being assessed. Although bone marrow is usually the dose-limiting organ with current RAIT techniques (e.g., nuclides, chelates), the radiation dose to lungs, kidney and liver may make them critical sites (Brochud et al, 1988). In addition to our observations reported here, other investigators have shown, in animal experiments and clinical trials of RAIT, that the radiation dose to liver can be quite high (Langmuir and Sutherland, 1988;Buchsbaum et al, 1990).…”

Section: Discussionsupporting

confidence: 47%

Application of cytokine intervention for improved radio-antibody dose delivery

et al. 1997

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The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibodyinduced myelosuppression and allow either dose escalation of radio-antibody using 131 The potential efficacy of radiolabeled antibodies as a cancer therapeutic is dependent on the maximal tolerated dose (MTD) that can be achieved and on the frequency at which doses can be administered. Two factors influencing both the MTD and the dose frequency are the radionuclide and the form of immunoglobulin used.A variety of radionuclides are under investigation for radioimmunotherapy (RAIT), and several advantages and disadvantages of each have been reviewed (Goldenberg, 1993). The availability of each radionuclide and the physical characteristics vary, each radionuclide decaying at a characteristic rate, with the release of distinct radio-active emissions and with differences in the distance that their particles travel in tissue. The b decay from 131 I travels a relatively short distance (,1 mm), and its maximum energy of decay is only 806 keV. Other b-emitting radionuclides, such as 90 Y and 188 Re, have a higher maximum energy (2,270 and 2,120 keV, respectively) and diffuse their radiation effect over a larger distance within tissues, having maximum path lengths of up to a few millimeters. The objective in selecting a radionuclide for a particular therapeutic application is to maximize the tumor radiation dose while sparing radiation-sensitive tissues from circulating radiolabeled antibody (Ab). The choice of nuclide, therefore, is in part dependent on (i) tumor size, which affects cross-fire and the energy-absorbed fraction, and (ii) binding heterogeneity (Humm, 1986;Howell et al., 1989). Shorter-range emitters are considered appropriate for smaller tumor masses since they maximize local energy deposition. For larger tumor burdens (diameter .1 cm), they would be unable to produce high enough dose levels in certain regions within the tumor that are antigen-negative or where the Ab is unable to penetrate.Selection of the form of immunoglobulin is another variable to be optimized for effective RAIT. Analysis of the pharmacokinetics of intact Ab and its fragments reveals a shorter plasma half-life (t 1/2 ) and less non-specific retention by non-tumor tissue of bivalent and monovalent fragments (Covell et al., 1986). As a result of the faster clearance rate of fragments, the radiation dose to blood is also much lower than that of the intact Ab. Therefore, a higher dose of radiolabeled fragment can be administered to a mouse (e.g., 1,200 µCi 131 I-F[ab8] 2 vs. 275 µCi 131 I-IgG).Unlike external beam irradiation, radiation energy in RAIT is imparted at a low dose rate over several days to weeks to tissues from internally distributed sources. The total radiation dose delivered and the rate of energy deposition in individual tissues are determined by the biodistribution of the administered radionuclide and the physical characteristics of the emitted particles. Among many influential variables, Ab biodistribution is...

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Section: Discussionsupporting

confidence: 47%

Application of cytokine intervention for improved radio-antibody dose delivery

et al. 1997

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“…84 The GM-CSF-induced leukocytosis which increased in magnitude after repeated administration was due White blood cell subsets and neutrophil kinetics to increased numbers of eosinophilic and neutrophilic granulocytes and monocytes. [85][86][87] Bone marrow cellularity and Administration of pharmacological doses of G-CSF and GM-CSF to humans or animals resulted in a triphasic response: [70][71][72][73][74][75][76][77] (1) myeloid/erythroid ratios also increased during GM-CSF therapy. 76,85 In patients with congenital, cyclic and chronic neuMarket neutropenia occurring approximately 5-60 min after injection (depending on the mode of administration); (2) Leutropenias, G-CSF treatment was more effective in increasing the ANC than treatment with GM-CSF.…”

Section: Effects Of Pharmacological Doses Of G-csf and Gm-csf Onmentioning

confidence: 99%

“…This is true for G-CSF-induced neutrophils from patients with severe congenital neutropenia 107,108 and glycowith cancer and healthy volunteers have shown a decreased migration 70,72,[91][92][93] which was related to the dose of G-CSF in genosis type IB (GSD IB) 11,14,109 which have been described to show moderate to severe impairment of their chemotactic one study. 70 During continuous intravenous infusion of GM-CSF, a markedly reduced neutrophil motility was found in a response towards a variety of chemoattractants in vitro.…”

Section: Impaired Chemotaxis Prior To G-csfmentioning

confidence: 99%

“…Furthermore, a decreased nuclear lobulation showing nuclear immaturity 82,88,106 and hypogranularity 88 were LAP score lasting from 0.5 to 4 h after injection followed by a strong increase reaching a peak level of 48 h after injecpresent in G-CSF-induced neutrophils. Neutrophils with increased diameter were identified by conventional light tion 71,72,82 (Table 4). The initial decrease in the LAP score is probably caused by a sequestration of neutrophils with higher microscopy 88 and by an increased forward angle light scatter intensity in flow cytometric studies 154 in G-CSF-treated LAP activity from the bloodstream, 111 whereas cells with lower activity are left in the circulation.…”

Section: Impaired Chemotaxis Prior To G-csfmentioning

confidence: 99%

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Functional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications

et al. 1997

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“…Myelosuppressive effects of chemotherapy can be mitigated in part by use of recombinant haemopoietic growth factors which stimulate the proliferation and maturation of haemopoietic cells in the bone marrow (Bronchud et al, 1988;Groopman et al, 1989;Hermann et al, 1989). One of these factors, rG-CSF, stimulates granulocyte proliferation in vivo (Souza et al, 1986;Cullor et al, 1990) and when given by continuous intravenous infusion, can reduce the duration of neutropenia in patients with chemotherapy induced myelosuppression (Bronchud et al, 1987; Recombinant human granulocyte stimulating factor (rG-CSF) was supplied by Chugai Pharmaceutical Company, Japan.…”

mentioning

confidence: 99%

High dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer

Ferguson

Dodwell²,

Seymour³

et al. 1993

Br J Cancer

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Summary Eighteen patients with advanced breast cancer were commenced on treatment with high dose doxorubicin (100mg m2) or doxorubicin (100 mg m-2) and cyclophosphamide (500 mg m-2) at 2 weekly intervals. Three cycles of treatment were planned. rG-CSF was given subcutaneously for 10 days, starting 24 h after each cycle of chemotherapy. Sixteen out of 18 patients responded (89%) of whom six (33%) achieved a complete remission. Twelve (67%) completed the three planned cycles, four (22%) received two cycles and two (11%) received one cycle only. The median time to progression was 51 months and the median survival was 18j months. Neutropenia occurred after 89% of courses and 65% of courses were accompanied by a significant (WHO grade III or IV) infection. The duration of neutropenia was short (mean 5.4 Gundersen et al., 1990;Jonsson et al., 1991). The response to conventional dose doxorubicin (60-70 mg m2 per 3 weeks) and to combination regimes containing doxorubicin are of the order of 50-60% (Carmo-Pereira et Steiner et al., 1983 and many others). At high doses () 100 mg m-2 per 3 weeks) response rates of over 80% have been reported in breast cancer patients (Jones et al., 1987(Jones et al., , 1990Bronchud et al., 1989). Cyclophosphamide shows a similar, if less dramatic increase in effectiveness at increasing doses (Bramwell et al., 1983;Frei et al., 1989).The importance of drug scheduling and dose intensity on efficacy and toxicity of treatment have been increasingly appreciated. When the total dose of two regimes are equivalent, the dose intensity may be of critical importance as exemplified by the lower efficacy of 35 mg m-2 doxorubicin (q 3 weeks x 16) when compared to 70 mg m2 doxorubicin (q 3 weeks x 8) (Carmo-Pereira et al., 1987). In a randomised study comparing the effect of scheduling on treatment outcome, there was no difference bet*een the equi-dose intensive regimes of doxorubicin 25 mg M2 (weekly x 12) versus 75 mg m-2 (3 weekly x 4 (Richards et al., 1992). The relative importance of these two parameters is unknown when high dose doxorubicin is used. In a previous study by Bronchud et al. (1989) The question then arises whether reducing the dose of doxorubicin further, whilst maintaining a dose intensive schedule would result in lesser toxicity without loss of treatment efficacy. To this end we have investigated the effects of doxorubicin given at 100 mg m2 at 2 weekly intervals in 18 patients with metastatic breast cancer. The first nine patients also received 500 mg m-2 cyclophosphamide and dose acceleration up to 2000 mg m-2 was intended. The epithelial toxicity of the combination chemotherapy appeared greater than expected and in consequence the remaining nine patients were treated with doxorubicin alone.The major toxicity of this regime was expected to be myelosuppression, particularly neutropenia. Myelosuppressive effects of chemotherapy can be mitigated in part by use of recombinant haemopoietic growth factors which stimulate the proliferation and maturation of haemopoietic cells in the b...

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In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients

Cited by 179 publications

References 21 publications

Application of cytokine intervention for improved radio-antibody dose delivery

Application of cytokine intervention for improved radio-antibody dose delivery

Functional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications

High dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer

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