PubMed Health⌕ Search

Biomedical subjects

M H Bronchud

Publications and source records attributed to M H Bronchud.

16 recordsLinked to original sources
PubMed2002

Is cancer really a 'local' cellular clonal disease?

Cancer is not simply the result of specific genetic alterations in key regulatory genes, but rather a complex multistep process involving selection of a clonal population of cells. To accumulate three, or often as many as seven, specific mutations in a single cell without incurring a significant number of additional mutations that might lead to cell lethality requires a large number of target cells, some mutagenic activity acting on those target cells for a variable period of time, and efficient selection strategies, which may be to some extent tissue-specific. A number of 'protective' intracellular regulatory circuits might be present in proliferating cells deliberately to protect against carcinogenesis. If it does require some seven sequential carcinogenic 'genetic hits' in a single cellular clone for a malignant tumor to develop, it is mathematically more likely to occur in a tissue with a high background of genetic alterations in neighboring cellular clones, than in a tissue with a low background of such alterations, or with no detectable carcinogenic mutations at all. In this context, the old 'field cancerization' theory by Slaughter and the more recent 'multistep carcinogenesis' model by Fearon and Vogelstein can come together in a single model: 'multistep field cancerization'. This simple conclusion, and our ability to measure 'background carcinogenesis' in different parts of the body, might allow early detection of cancer risk, and eventually help us to develop suitable therapeutic strategies to delay or suppress the carcinogenic process. Molecular technologies are just beginning to be sufficiently sensitive to start testing the hypothesis.

Adult↗
PubMed1993

The importance of dose: lymphomas as a model of chemosensitive malignancies.

Chemotherapy dose intensity is probably important to the success of treatment for some human malignancies. Recombinant human haemopoietic growth factors have recently become available to clinicians to ameliorate the myelosuppression that follows cytotoxic chemotherapy. Their use to increase the dose intensity of treatment, either by simply allowing the administration of the planned dose on schedule or by increasing the dose or dose rate above the conventional ones, is being actively investigated by several European and American groups. In several reported studies, neutropenia is no longer dose limiting when granulocyte colony-stimulating factor is used to help to intensify cytotoxic chemotherapy, but thrombocytopenia or mucositis are. The use of circulating haemopoietic progenitor cells, released into the blood stream by growth factors and infused with or without autologous bone marrow, has been reported to consistently reduce the overall period and severity of thrombocytopenia following intensive chemotherapy in patients without pre-existing severe bone marrow damage. However, no clear improvements in survival have yet been documented with the use of these techniques. Difficulties in study design include a number of variables potentially involved (tumour model, patient population, adjuvant or advanced disease, dose of cytotoxics, intervals, end-points, etc.), and there is clearly a need for more studies and longer follow-up. Lymphomas, both non-Hodgkin and Hodgkin's disease, are the prototypes of chemosensitive malignancies curable by chemotherapy alone even in disseminated disease. Therefore, they would seem to be adequate models to test the dose intensity hypothesis in the clinic. However, there are important differences between these two types of disorder. The success of conventional therapies in these conditions suggests that further improvements in outcome and long-term survival by further increases in dose intensity with current drugs will require careful study designs, due attention to prognostic factors, and reasonable expectations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.

Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC infinity with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.

Adult↗
PubMed1990

Ifosfamide, doxorubicin and etoposide in small cell lung cancer patients with poor prognosis.

61 patients with small cell lung cancer in a poor prognosis group were treated with chemotherapy and with thoracic radiotherapy if they had 'limited stage' disease. No prophylactic cranial irradiation was given. Chemotherapy comprised doxorubicin 50 mg/m2 and ifosfamide 5 g/m2 with mesna on day 1, and etoposide 120 mg/m2 intravenously on days 1 and 2 and 240 mg/m2 orally on day 3. Treatment was repeated every 3 weeks for a maximum of six courses and no dosage reductions were allowed. Complete response rate in limited stage patients was 55% and 16% in extensive stage patients. The partial responses were 38% and 66% respectively. Overall median survival was 10.5 months with 2-year survival of 14%. The corresponding values for limited stage disease were 13 months and 16% and for extensive stage disease 8 months and 13%. Despite the addition of doxorubicin at a somewhat higher dosage than usual in this type of regimen and a policy of no dose reduction, toxicity was generally mild. There was, however, a 19% relapse rate in complete responders in the brain, apparently as the sole site of disease.

Adult↗
PubMed1989

Clinical use of haematopoietic growth factors.

Over the past decade experimental haematologists have identified and eventually characterised a number of polypeptide growth factors capable of stimulating the proliferation and differentiation of haemopoietic progenitor cells in vitro. The molecular cloning of these growth factors has now allowed their use in vivo, and some of them have shown promise in recent clinical trials. Most of the work has been done on erythropoietin and myeloid growth factors, which are discussed in this review. Erythropoietin has been used successfully as replacement therapy in the anaemia of end-stage renal failure, but may also prove clinically useful in other chronic anaemias and, in combination with other growth factors, as a stimulant of bone marrow regeneration following bone marrow transplant. Myeloid growth factors, and, in particular, granulocyte colony-stimulating factor, have been shown to accelerate neutrophil recover in cancer patients following chemotherapy, with a reduction in the number of severe infections and mucositis.

Colony-Stimulating Factors↗
PubMed1989

The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer.

Granulocyte colony stimulating factor (G-CSF) was given to 17 patients with advanced breast and ovarian cancer in order to increase the intensity and effectiveness of chemotherapy. Treatment with doxorubicin, at doses of 75 mg m-2 (n = 4 patients), 100 mg m-2 (n = 5), 125 mg m-2 (n = 6) and 150 mg m-2 (n = 2), was followed by infusion of G-CSF for 11 days. G-CSF administration resulted in a return of the absolute neutrophil count to normal or above normal levels within 12-14 days at all dose levels of doxorubicin used and allowed the administration of up to three cycles of high dose chemotherapy at 14 day intervals. An absolute neutrophil count greater than 2.5 x 10(9)l-1 was not reached until day 19-21 after 75 mg m-2 of doxorubicin given without G-CSF. At doses of doxorubicin of 125 mg m-2 and 150 mg m-2 all tumours regressed rapidly, although there was marked epithelial toxicity. The overall response rate in patients with advanced breast cancer was 80% with a median time to progression of 6 months. Two months after doxorubicin-G-CSF therapy there was a pronounced improvement of symptoms compared with before treatment. Thus the effectiveness of chemotherapy may be enhanced and treatment duration shortened by the use of G-CSF infusions. Further studies of this promising approach are warranted.

Adult↗
PubMed1989

The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo.

Cell proliferation in the bone marrow and blood of two patients with metastatic breast cancer who were treated with granulocyte colony-stimulating factor was studied by using [3H]thymidine labeling and autoradiography. Additionally, the fate of neutrophils labeled with 99mTc-hexamethylpropyleneamineoxime was observed following granulocyte colony-stimulating factor infusion. Proliferation increased in all stages of granulopoiesis, but a significant amount of the increased production stemmed from a greater input to the myeloblast compartment. Changes in the myelogram combined with the increased labeling indicated a faster throughput of cells, which resulted in labeled cells appearing in the circulation within 1 day compared to the normal 4 or 5 days. The 99mTc studies demonstrated no sequestration of circulating neutrophils by spleen, lungs, or liver. The half-life of the circulating neutrophils was not significantly changed, and calculations from the flow of labeled cells to the peripheral blood indicated an increase of 3.2 extra amplification divisions during neutrophil development. The dramatic neutrophil response to granulocyte colony-stimulating factor can therefore be accommodated by a relatively modest increase in granulopoietic activity.

Adult↗
PubMed1989

Clinical use of growth factors.

Cellular proliferation and differentiation in the living organism are regulated, at least in part, by a complex network of interacting peptides, or growth factors. The purification and molecular cloning of these growth factors has now led to the exciting task of ascertaining their physiological role in vivo and to verify their value as therapeutic substances worthy of clinical use. Rigorous methods of drug evaluation are required to prove the efficacy and safety of these new biological agents, particularly now that so many of them are being produced by the new genetic engineering techniques. Haemopoietic growth factors and growth factors involved in the regulation of the immune response have been more extensively studied clinically and are discussed in this section.

Anemia↗
PubMed1988

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

Twelve patients with small cell lung cancer were treated with recombinant human granulocyte colony-stimulating factor, rhG-CSF, given by continuous infusion at doses ranging from 1 to 40 micrograms kg-1 day-1. Patients received the rhG-CSF before the start of intensive chemotherapy and after alternate cycles of chemotherapy. Several in vitro assays were performed using peripheral blood neutrophils and marrow progenitor cells collected from patients prior to and after infusion of the growth factor. Peripheral blood neutrophils were tested for mobility and phagocytic activity. In addition, in vitro clonogenic assays of marrow haemopoietic progenitor cells and analysis of bone marrow trephines and aspirates were carried out. We found that rhG-CSF in vivo has at least two main effects: (a) an early fall in peripheral neutrophils, within the first hour, followed by a rapid influx of mature neutrophils into the circulatory pool; (b) stimulation of proliferation and differentiation of neutrophil precursors in the bone marrow. Neutrophils released into the circulation were normal in tests of their mobility and phagocytic activity.

Antineoplastic Agents↗
PubMed1987

Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer.

Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rhG-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms kg-1 day-1 for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9) l-1 at 10 micrograms kg-1 day-1. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the phase II part of the study the patients were treated by a combination of intravenous adriamycin 50 mg m-2, ifosfamide 5 g m-2 by i.v. infusion with mesna 8 g m-2 on day 1, and etoposide 120 mg m-2 on days 1, 2 and 3 also intravenously. The chemotherapy regime was repeated every 3 weeks. RhG-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Six severe infective episodes were observed during the cycles of chemotherapy which did not include rhG-CSF, while no infective episodes occurred when patients were treated with rhG-CSF. These results demonstrate the utility of rhG-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.

Aged↗
PubMedDate not supplied

Recombinant human granulocyte colony-stimulating factor in the management of cancer patients: five years on.

Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used worldwide in cancer patients for over 1 year, and (only 5 years from the first publication on the clinical use of this growth factor) experience is rapidly accumulating in many oncological situations. Several randomized studies have confirmed its value in allowing the optimal delivery of chemotherapy without undue dose reductions or dose delays, while at the same time reducing the overall risks of febrile neutropenia associated with the use of cytotoxic chemotherapy. Its virtual lack of significant side effects, its selectivity of action, its rapid effect on neutrophil kinetics (reducing both the maturation and release times of bone marrow neutrophils to 1-2 days rather than the normal 4-5 days), and the reproducible augmentation of neutrophil production in several neoplastic and nonneoplastic situations, as well as the activation of myeloid cell functions, have made G-CSF the growth factor of choice in most cancer units. Some of the published information regarding its current and potential use in the management of oncological patients is summarized here.

Antineoplastic Agents↗