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Biomedical subjects

G Mathé

Publications and source records attributed to G Mathé.

At least 145 records · Page 8Linked to original sources
PubMed1988

Hematon: a multicellular functional unit in primary hematopoiesis.

Bone marrow aspirates from healthy donors contain a fraction of low density multicellular spheroids, 100-500 microns in diameter. They are organized in a three-dimensional network consisting of central preadipocytes/adipocytes, mesenchymal and reticular cells, and resident macrophages that are closely associated with myeloid, erythroid and megakaryocyte progenitor cells and with their progenies. These spheroids are 2- to 5- fold more abundant in progenitor cells compared with the whole bone marrow as estimated by monoclonal antibody markers My 10 and T 9, by analysis of granulocyte--macrophage colony forming cells (GM-CFC) and by cytological techniques. They produce terminally differentiated cells in organotypic microcultures. We suggest that a multicellular spheroid may represent the fundamental unit of primary hematopoiesis; we therefore name it hematon. Here we show that the presence of hematons in bone marrow aspirates correlated positively with homeostatic blood cell production: they were present in normal bone marrow (BM) (19/25), and absent in myelodysplasic syndromes (MDPS) (8/21), in acute nonlymphocytic leukemias (ANLL) (3/22) and in chronic myeloid leukemia (CML) (2/28). The hematons were recovered under hematological remission in MDPS and in ANLL, suggesting that they may be dispersed reversibly in certain disease conditions. The hematons represent a unifying model around which the variability in some bone marrow cell functions can be explored.

Bone Marrow↗
PubMed1988

On a new class of mixed-function drugs associating nitroimidazoles and CENU: the NICE-NU.

Two series of (2-chloroethyl) nitrosoureas (NICE-NU) bearing a nitroimidazole group have been synthesized for anti-tumor evaluation with the aim of chemopotentiation of their biological activity. Their anti-tumor activity against L1210 in vivo in mice is excellent especially for the series A derivatives where a hydroxy function provides assistance to decomposition. However, the activity of NICE-NU against B16 melanoma is lower.

Animals↗
PubMed1987

A comparative trial of a MAOI, iproniazide, and a polycyclic agent, mianserine, for the search of the most rapidly and frequently active treatment of depressive syndromes in an oncology service.

Many cancer patients of the "Service des Maladies Sanguines et Tumorales" of Hôpital Paul-Brousse, Villejuif, are psychologically studied by: the objective and quantified Szondi test, and in the case a depressive syndrome clinical diagnosis is confirmed, this state is quantified by a quintile questionnaire requiring 25 "yes or no" answers (determined by five grades and five stages), in case an inhibition or/and hysteric component is found, the subjects are submitted to the care of a psychoanalyst. A comparative trial of the MAOI, iproniazide, and the tetracyclic analog, mianserine, has been conducted for the search of the most frequently and rapidly active antidepressant agent among them both. The hypothesis that mianserine is less frequently and rapidly active than iproniazide was drawn from our previous experience of 20 years: thus patients presenting a score less than or equal to 12/25 were given mianserine (20 up to 30 mg/day to be possibly increased according to medical decision), while those presenting a score greater than or equal to 13/25 received iproniazide (50 up to 75 mg/day). The patients who failed with mianserine received iproniazide, while those who failed with iproniazide were supposed to receive mianserine. The registered results are the following: a) out of the 25 patients with major depressive syndromes (score greater than or equal to 13) submitted to iproniazide, 16 (61%) were in complete remission (score at 0/25) and five in partial regression (score decreased by more than half); this makes 21 responses in all, i.e. 80%, obtained between the 10th and the 30th days, which is superior to all placebo responses which have varied in the reliable literature from 13 to 70%; b) out of 18 depressive patients submitted to mianserine, only one had benefited of a complete remission and four of a partial regression at the 30th day, which makes 28% responses. Among the side effects of iproniazide, they were two colon meteorism syndromes, easily corrected by prostigmine, five hyposomnia cases corrected by dipotassium chlorazepate, four anejaculation or delay at ejaculation cases which needed eserine when the patients require their disappearance or attenuation. We did not register either hepatic or hyperthermic or hypertensive complications: this is in good agreement with the true incidences, especially that of hypertensive crisis which could be found in serious and scientifically documented articles, to be 0.3 to 0.5% for their appearance, and 1 per 100,000 for their fatal evolution. Among the side effects of mianserine, we have not registered any of the hepatic, renal and cardiac complications mentioned in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents, Tricyclic↗
PubMed1987

Passive, adoptive, and active immunotherapy: a review of clinical trials in cancer.

The results today of passive immunotherapy with monoclonal antibodies (MAb) are still very limited, even via its indirect methods (in vitro tumor cell clearance of bone marrow before autologous retransplantation, transport of cytostatic chemicals, and radiation). Tumor cell heterogeneity requires the use of several MAb. Adoptive immunotherapy in the form of the graft vs leukemia (GVL) reaction associated with the graft vs host (GVH) reaction, after an allogeneic bone marrow transplantation, first demonstrated in animals in 1962, has been confirmed in man. The material and operational development of tumor immunology, immunopharmacology, and clinical trial methodology should improve active immunotherapy results and help to convert into a cure what is often a significant but only marginal increase: 1) of disease-free survival or 2) of survival or 3) of survival after relapse. The general ineffective management and use of adjuvant chemotherapy for all tumors except breast carcinoma before menopause will, on the other hand, contribute to necessary new concepts of how to manage the postremission, residual, minimal disease.

Clinical Trials as Topic↗
PubMed1987

Do tuftsin and bestatin constitute a biopharmacological immunoregulatory system?

Tuftsin is the tetrapeptide Thr-Lys-Pro-Arg. It is spontaneously released from the Fc fragment of IgG by two specific enzymes. One 25-micrograms dose administered to mice in good immunologic status stimulated phagocytosis, macrophage killing of tumor cells, delayed hypersensitivity, cytolytic T-cell activity, antibody production, antibody-dependent cell-mediated cytotoxicity (ADCC), and natural killer (NK) cell activity. Administered for 6 months at the dose of 10 micrograms once a week to old, immunodepressed mice, tuftsin restored macrophage and T-cell cytotoxic activities. At this dosage, tuftsin prevented spontaneous tumor development. Tuftsin was also well tolerated in phase I studies in humans in increased polymorphonuclear leukocytes and OKT4-positive lymphocytes. Bestatin is extracted from Streptomyces olivoreticuli. One 100-micrograms dose of bestatin injected in young mice with normal immunologic status increased macrophage cytotoxicity, antibody production, ADCC, and NK cell activities. Long-term administration of bestatin (100 micrograms once a week) corrected macrophage and T-cell cytotoxicity and prevented age-related spontaneous tumors. Bestatin inhibited lymphocyte membrane aminopeptidase, which degrades tuftsin into a tripeptide that is an antagonist competing with it for receptors. Tuftsin and bestatin constitute a biopharmacologic system that can be developed as other aminopeptidase inhibitors are available for study.

Adjuvants, Immunologic↗
PubMed1987

[Objective response of desmoid fibroma to chemotherapy].

Six patients with inoperable desmoid tumors have been treated by preoperative chemotherapy. In all six cases objective response occurred and allowed conservative surgery. Objective responses included tumor softening (6/6), releasing of articular motion previously limited (3/3), and tumor size' decreasing (2/6). Few histologic modifications were seen. Such data advocates for preoperative chemotherapy in desmoid tumor when large and threatening the limb or the life of the patient.

Adolescent↗
PubMed1986

Phase II trial with D-Trp-6-LH-RH in prostatic carcinoma: comparison with other hormonal agents.

Various approaches to hormonal treatment of prostate carcinoma are discussed. Eighty-one patients with prostatic carcinoma, eight with stage B, nine with stage C, and 64 with stage D disease, were treated subcutaneously daily for 3 months with the LH-RH agonist D-Trp-6-LH-RH (Decapeptyl) in order to evaluate the incidence of remissions according to WHO recommendations for oncologic trials. The findings were compared to those obtained with other hormonal therapies of prostatic carcinoma according to the statistical method of "expected response rate" as adapted by Lee and Wesley for phase II trials. Treatment with D-Trp-6-LH-RH greatly reduced serum LH and testosterone levels without raising serum prolactin. After 1-2 weeks of therapy, there was relief of subjective symptoms and a reversal of the signs of prostatism as well as a marked decrease in bone pain. At 90 days 52 patients had complete relief of prostatism and 21 had only mild signs and symptoms. Seventy patients were experiencing no bone pain and an additional six had only mild pain. Prostatic size, evaluated by rectal examination and transabdominal ultrasonography, reverted to normal in 26.4% of patients (complete remission) and was reduced by more than 50% in an additional 17.6% (partial remission), the overall rate of complete plus partial regression of prostatic enlargement being 44%. Scans showed a major improvement of bone lesions in 14.8% of cases. This response increased to 37% after more than 6 months of follow-up. Prostatic acid phosphatase levels were decreased by more than 50% in 61% of the patients, but this test appears to be a less valid marker than the lipid-associated sialic acid (LASA). The increase in LASA before treatment and a reduction after treatment can frequently be correlated with the objective volume of the neoplasms. No flare-up of the disease was encountered, and there were no side effects except for impotence. Statistical analyses of results by the method of Lee and Wesley indicated that the incidence of complete and partial regression (CR and PR) observed with D-Trp-6-LH-RH was not significantly different from that recorded in previous studies for another LH-RH analog, Buserelin. However, CR and PR obtained with D-Trp-6-LH-RH (44%) were significantly higher than with subcapsular orchiectomy (22%). Hormonal effects and some other actions of D-Trp-6-LH-RH were compared and contrasted with those produced by castration, estrogens, antiandrogens, and progestogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗
PubMed1986

From experimental to clinical attempts in immunorestoration with bestatin and zinc.

Severe impairment of the lymphopoietic cell renewal system is an important etiological factor of cancer development and it may be the consequence of massive radio and/or chemotherapeutic regimens. In a comparative study, we analysed the potential, systemic immunorestoratory capacity of bestatin, a microbial leucil-aminopeptidase inhibitor and of the ubiquitous trace element zinc. In vivo administration of bestatin in mice stimulated both Interleukin 1 and Interleukin 2 production, and enhanced T cell, B cell as well as macrophage mediated immunoreactions. In a phase II clinical trial on 41 patients with non-Hodgkin lymphoma, Hodgkin disease and solid tumors, bestatin treatment corrected the pathological frequency of both OKT4 and OKT8 lymphocyte subpopulations. Zinc-saturated transferrin had a significative stimulatory effect on the ongoing DNA synthesis of antigen activated human lymphocytes in culture. Oral administration of zinc-gluconate to patients who manifested a severe T cell subpopulation defect corrected preferentially the OKT8 suppressor/cytotoxic T cell unbalances. The clinical results obtained by both bestatin and zinc were observed only on a short-term, so further studies are needed to elaborate long lasting regiments and to establish whether these treatments have determinant influence on the underlying disease.

AIDS-Related Complex↗
PubMed1986

Cytostatic action of two nitrosoureas derived from cysteamine.

2-Chloroethyl nitrosocarbamoylcystamine or ICIG-1325 (CNCC) is a lipid-soluble isomeric mixture of nitrosoureas. Its dose-effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose-range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG-Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2-[3-(2-chloroethyl) 3-nitrosoureido]D-glucopyranose (CZT), (chloro-2-ethyl)-1(ribofuranosyl-isopropylidene-2'-3' paranitrobenzoate-5')-3 nitrosourea (RFCNU), and (chloro-2-ethyl)-1 (ribopyranosyl triacetate-2'-3'-4')-3 nitrosourea (RPCNU). A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first-pass metabolism leading to the formation of four main plasma metabolites. These metabolites are water-soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. Experimental screening was performed with these chemically synthesized metabolites. Both N'-(2-chloroethyl)-N-[2-(methylsulphinyl)ethyl]-N'-nitrosourea (CMSOEN2) and N'-(2-chloroethyl)-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (CMSO2EN2) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition,the percentage of mice cured after CMSOEN2 or CMSO2EN2 treatment is increased especially on B16 melanoma and glioma 26. 6 Haematological toxicity of both active metabolites is lower than that of CNCC, particularly on platelets which is the main toxicity location due to nitrosoureas.

Animals↗
PubMed1986

Phase I study of cis-dichloro-trans-dihydroxy-bis(isopropylamine)platinum IV (CHIP).

Cis-dichloro-trans-dihydroxy-bis(isopropylamine)platinum IV (CHIP) is a second-generation cis-platinum (DDP) derivative with an octahedral conformation of the platinum complex, far more water-soluble than DDP. Tests in numerous murine tumor systems demonstrate a spectrum of activity similar to that of DDP. A phase I study of CHIP using 5 consecutive daily 1-hour infusions without pretreatment hydration or diuretics was completed at Hospital Paul-Brousse, Villejuif, France. 16 patients received a total of 28 courses of CHIP. In 11 of them hematologic toxicity could be assessed. The starting dose, 20 mg/m2/day X 5, was increased to 30, 45 and 50 mg/m2. There was neither renal nor neurotoxicity. Nausea and vomiting were constant but usually mild or moderate. No diarrhea was seen. Myelosuppression was dose-limiting with a mean polymorphonuclear cell (PMN) count nadir of 2.4 X 10(3)/mm3 (range 1 X 10(3)-3 X 10(3)/mm3) and a mean platelet count nadir of 110 X 10(3)/mm3 (range 60 X 10(3)-180 X 10(3)/mm3) at the recommended dosage of 45 mg/m2/day X 5. The drug should be given every 6 weeks because of the late platelet nadir. A total of 13 patients are evaluable for efficacy. One histologically documented complete response lasting more than 12 months was observed in a patient with an ovarian carcinoma.

Adult↗
PubMed1986

Managing minimal residual malignant disease.

So-called complete remission of acute leukemia and other tumors frequently leaves minimal residual disease cells, sometimes causing an inflammatory response and often relapse. Although the remaining cells often have long generation times or may even be in G0 condition, they may form a new tumor mass. This can be explained by cell kinetics alone, or by an escape from immunologic or other control mechanisms, or by a new promoting event. Maintenance chemotherapy beyond the first 6 months seemed only to have an effect where induction chemotherapy was weak and palliative, but not since it has become intensive and sometimes curative: it only increases the relapse incubation time, not the survival. Relapse cells may be refractory to cytostatics previously not given, in part because of alternative metabolic pathways or enzyme induction, in part because of tumor cell progression, and any chemotherapy seems to be able to play a significant role in this progression. The result is a relatively high residual tumor mass and a short duration of rare second remissions. Adjuvant immunotherapy, despite controversies about its results, seems to work in some tumors, but the statistical methods applied and the monitoring have been criticized. The strategy proposed for potentially 'curable' tumors (leukemias, lymphomas, embryomas) with short cell generation times is therefore intensive remission induction aiming at the smallest possible residual disease cell number. It is conceivable that this induction might mean accepting risks comparable to those accepted for transplant patients. Manipulation of the bioimmunological response can be effective even against cells in the G0 phase. New methods are proposed to manage residual disease of solid tumors with long generation times, and only maintenance chemotherapy active on cells with a long generation time is suggested.

Humans↗
PubMed1986

Curve models for comparative phase III trials: heterogeneity of the population.

Equations were calculated to describe survival on disease-free survival (DFS) curves related to control or adjuvant-therapy-treated patients. They allowed us to differentiate three different segments or populations in the survival curve on a semi-log scale describing high-risk, intermediate-risk and low-risk groups. The percentage of patients and the annual mortality in each risk group could be calculated from the coefficients of the equation. As an example, the DFS curves of the premenopausal breast cancer patients of the Milan group were composed of three segments in the control group and of two segments in the CMF-treated group.

Breast Neoplasms↗