Biomedical subjects

V Quemener

Publications and source records attributed to V Quemener.

64 records · Page 4Linked to original sources

PubMedDate not supplied

In vivo antitumor activity of 4-amino 4-methyl 2-pentyne 1-al, an inhibitor of aldehyde dehydrogenase.

4-amino-4-methyl-2-pentyne-1-al (AMPAL), a new irreversible inhibitor of aldehyde dehydrogenase (ALDH) has been assayed for its in vitro and in vivo antitumor activity. In vitro, AMPAL inhibits the proliferation and the ALDH activity of L1210 and RBL5 cell lines. In vivo, AMPAL significantly increases the mean survival time of mice i.p. grafted with leukemia (L1210, P815, MBL2, EL4, RBL5 cell lines) or carcinoma cells (Krebs cell line), without haematopoetic toxicity. No carcinostatic effect was observed against the P388 leukemia and the 3LL Lewis lung carcinoma. A possible relationship between the ALDH isoenzyme activity of the tumor and its sensitivity to AMPAL is discussed in the light of previous reports concerning the role of aldehydes in cell growth control.

Aldehyde Dehydrogenase↗

PubMedDate not supplied

Clinical importance of erythrocyte polyamine level determination during bone marrow transplantation in children.

Previous studies have shown that red blood cell (RBC) spermidine (Spd) and spermine (Spm) concentrations appear to be a reliable index of cell proliferation. Our aim was to study the RBC polyamine level evolution (Spd and Spm) in bone marrow (BM) transplanted children. Because of our interest in the finding of an early blood criteria of BM regeneration, our study was based upon the chemotherapy - induced post-transplant aplasia period. After BM transplantation, two main periods were observed: the first (A-period) corresponded to abnormally low Spd levels. This period ended with an increasing amount of Spd reaching normal values and with an inversion in the Spd/Spm ratio which became greater than 1. The second (B) period was usually linked to abnormally high RBC Spd concentrations and a Spd/Spm ratio greater than 1. The end of the B-period was characterized by an increase in the granulocyte count (reaching 0.5 X 10(9) cells/l). Since the A- and B-periods are considered as a post-transplant aplasia period (only according to leukocyte count) and since normal RBC Spd levels occurred 14 days (SD = 4) after BM transplantation and 16 days (SD = 12) before granulocyte rise, these data led us to consider erythrocyte polyamine levels to be an earlier biological criteria of bone marrow engraftment than the number of circulating granulocytes.

Adolescent↗

PubMedDate not supplied

Spermidine uptake by erythrocytes from normal and Lewis lung carcinoma (3LL) grafted mice: I. In vitro study.

High red blood cell (RBC) spermidine levels have been observed in patients harboring various histological types of cancer. In an attempt to explain the mechanism of RBC spermidine uptake in the malignant cell growth process, erythrocytes from normal and (3LL) Lewis lung carcinoma grafted mice were incubated with [14C] spermidine in the presence of PBS or plasma from normal or 3LL grafted mice. Though RBC of cancer mice harbor abnormally elevated spermidine concentrations as compared with those of controls, when incubated with PBS, 3LL grafted mice exhibit [14C] spermidine uptake three times higher than that of normal mice erythrocytes in the same incubating conditions. Moreover, if plasma incubations always increase spermidine uptake in RBC from cancer mice compared with erythrocytes only incubated with PBS, plasma incubations are responsible for two opposite effects in RBC of normal mice: plasma increases spermidine uptake in PBS unwashed erythrocytes and lowers it in PBS washed RBC. One possible explanation for the observed plasma stimulating effect in RBC spermidine uptake might be the presence of a plasma component common to plasma from normal and cancer mice, able to interact with RBC membrane proteins. In erythrocytes from cancer mice, the high spermidine concentration would be responsible for the observed compactness in band 3 proteins involved in ionic transport through RBC stroma. In normal mice erythrocytes which exhibit low polyamine levels, the observed dissociation of band 3 proteins might explain the spermidine uptake in PBS washed normal RBC incubated with plasma. In vivo, this plasma component would participate in the stabilization of normal mice membrane proteins involved in RBC spermidine uptake.

Animals↗

PubMedDate not supplied

Spermidine uptake by erythrocytes from normal and Lewis lung carcinoma (3LL) grafted mice: II. In vivo study.

During Lewis lung carcinoma (3LL) growth, red blood cell (RBC) spermidine (Spd) level evolution was proportional to the increase in tumor volume and inversely correlated with the decrease in tumor Spd concentration. Similarly, in cancer mice i.p. injected with [14C] Spd, the increasing amount of erythrocyte [14C] Spd was in proportion with tumor volume enhancement and linked to decrease in tumor tissue [14C] Spd concentration. After i.p. injection of [14C] Spd putrescine or [14C] spermine, contrary to normal mice, cancer mice provided [14C] Spd in their erythrocytes. When injected with [14C] methionine, [14C] polyamines were never found in normal or cancer mice erythrocytes. As previously noted in vitro, increasing amounts of polyamines produced by tumor tissue and excreted into blood would modify erythrocyte stroma proteins involved in the RBC [14C] Spd uptake process. These data obtained in vivo demonstrate the tumor origin of polyamines carried by erythrocytes. Since RBC polyamine levels are directly correlated with tumor progression, these experimental results reinforce the clinical use of this index of cell proliferation in malignant diseases with a short doubling time.

Animals↗

PubMedDate not supplied

Red blood cell polyamines as biochemical markers of supratentorial malignant gliomas.

Data obtained during post-surgical monitoring (2 to 28 months) of 32 histologically confirmed malignant supratentorial glioma patients, are reported here. It was observed that: whatever the grade of malignancy, 100% of the patients whose tumor recurred showed, on at least one occasion, abnormal red blood cell (RBC) spermidine (SPD) (greater than 14 nmoles/8.10(9) RBC) or spermine (SPM) (less than 2 nmoles/8.10(9) RBC) levels. 30% of the patients whose tumor recurred had abnormal RBC polyamine concentrations, one to six months before any other sign of tumor progression. In patients with normal RBC polyamine values, clinical and tomodensitometric indications of tumor progression have to be reconsidered. During individual follow-up, RBC SPD levels of each patient were generally significantly correlated to those of SPM, and the slopes of their straight regression lines (SRL) appeared to be related to the importance of the intracranial cell proliferation. In such conditions we established the regression equation of the group of all recurring patients taken together. We propose a graphic model, including a space corresponding to RBC SPD and SPM levels observed in case of tumor recurrence, which can be utilized routinely in neuro-oncology during the monitoring of post-operative malignant supratentorial glioma patients.

Adult↗

PubMedDate not supplied

[The involvement of polyamines in the malignant proliferative process. The anticancer effect of polyamine deprivation].

The fact that tumors require polyamines for growth has been repeatedly demonstrated. In vivo polyamines are available both from endogenous (intracellular biosynthesis) and exogenous sources (food and intestinal microflora). We investigated in rats grafted with Mat-Lylu prostatic adenocarcinoma the distribution between tumor and tissues of orally administered (14C) putrescine (Pt). The amount of radioactivity retained by tumors was directly proportional to the tumor volume. In a tumor of 25 cm3 19% of the totally retained radioactivity was found. The accumulation of Pt by intestinal brush-border membrane vesicles prepared from tumor-bearing animals was significantly higher than by vesicles from healthy rats. Our results indicate that the presence of a tumor induces an adaptive response in the small intestine which stimulates the uptake of exogenous polyamines. Our therapeutic strategy was to realise a total blockade of all endogenous and exogenous sources of polyamines by feeding animals with a drug (DFMO, MDL 72527, antibiotics) containing polyamine deficient chow. We observed that polyamine deprivation largely reduced both primary tumor and metastatic development. Natural Killer cell cytotoxic activity and blood formula were restored to normal values after treatment. Furthermore polyamine deprivation enhanced anti-tumoral efficacy of chemotherapy.

Adenocarcinoma↗

PubMedDate not supplied

Polyamine deprivation: a new tool in cancer treatment.

The fact that tumors require polyamines for growth has been demonstrated in vitro and in vivo and widely reported. This finding led to the use of polyamine biosynthetic enzymes as targets for antitumor drug design. Highly efficient in vitro selective inhibitors of ornithine decarboxylase such as DFMO do not produce important antitumoral effects in vivo, due to the ability of tumor cells to uptake extracellular polyamines. A new strategy was developed, combining a systematic blockade of all endogenous and exogenous sources of polyamines in vivo. Sources of exogenous polyamines were eliminated by administration of a polyamine-free diet to the animals and decontamination of their gastrointestinal tract. Important antitumoral effects were obtained with this polyamine deprivation and are presented with two experimental models of tumors (Lewis lung carcinoma, Mat Lylu prostatic carcinoma). Biological parameters, modified in cases of cancer, were restored to normal values in treated animals: blood counts and NK cytotoxic activity. Number of metastases was significantly reduced. Given that in man cancer treatment remains unsatisfactory due to incomplete cell kill, development of resistance to treatment and secondary effects of chemotherapy, we chose to investigate the potential interest of polyamine deprivation in this field. By combining clinically applied cytotoxic drugs with polyamine deprivation, we observed an improvement of their antitumoral efficiency: a considerable retardation of tumor growth paired with a marked increase in life-span of the treated animals. Our observations confirm that polyamines absorbed from exogenous sources, mainly food and gastrointestinal tract, play an important role in tumor growth control. Furthermore, the study shows that polyamine deprivation represents an important potential therapeutic tool in improved management of cancer treatment.

Animals↗

PubMedDate not supplied

Polyamine deprivation stimulates natural killer cell activity in cancerous mice.

It has recently been established that the total blockade of all endogenous and exogenous sources of polyamines by a drug containing polyamine deficient chow (DC-PDC+) could inhibit tumor growth in vivo and increase the antitumoral efficacy of chemotherapy drugs. We show here that polyamine deprivation obtained with DC-PDC+ not only influences tumor development via reduction of polyamine concentrations in the tumor itself but, in addition, stimulates cells of the non-specific immune system specialized in tumor cell killing. We report that mice grafted with the 3LL carcinoma present a dramatic decrease in the cytotoxic activity of their natural killer (NK) cells. When these animals are treated with DC-PDC+, their NK cell activity is completely restored to normal values. Normalization of leucocyte number and differential count was observed as well. With respect to the different components of the DC-PDC+, it was observed that the endogenous and exogenous sources of polyamines have a different degree of impact on tumor development. For example, when only polyamines from digestive sources are deprived, a weak but significant improvement in NK activity and antitumoral effects were observed, without affecting intra-tumoral polyamine concentrations. We conclude that polyamines, secreted by the tumor itself as well as absorbed through the gastrointestinal tract, could now be considered not only as autocrine growth factors but also as natural immunosuppressive factors.

Animals↗

PubMedDate not supplied

Determination of erythrocyte polyamines as a predictive method in tumour diagnosis. An animal study with chemically induced tumours.

There have been numerous attempts in the past to use polyamine determinations in body fluids for tumour diagnosis. Since spermidine (Spd) and spermine (Spm) are mainly transported in blood by erythrocytes, this study was concerned with the diagnostic possibilities of red blood cell (RBC) polyamine determinations. In tumour-grafted animals we observed that RBC polyamine levels correlated with the tumour mass progression and increased before the tumour was palpable. Discrepancies between the evolution of RBC polyamine levels in tumour-grafted animals and in cancer patients were probably due to the non-continuous growth of the tumours in patients. Therefore, an animal model was sought which mimicked the clinical situation. In the present experiments, ethylnitrosourea induced tumours were used which, in analogy to the clinical situation, had an undetermined time of the appearance in a non-predetermined proportion of the animals. RBC polyamines were determined over a period of 7 months in 154 rats. A total of 2,290 RBC polyamine determinations were performed during this study. The data clearly demonstrate the appearance of elevated Spd concentrations in advance of tumour diagnosis by conventional clinical methods. In 71% of the rats which later developed a tumour, abnormal Spd levels (> 40 nmol/8.109 RBC) preceded, by 35 +/- 31 days, the first clinical symptoms for the presence of a tumour. In 29% of the animals, abnormal RBC Spd concentrations were observed at the time of tumour diagnosis. Elevation of Spm concentrations (> 6 nmol/8.10(9) RBC) was less frequent. RBC polyamine levels did not allow discrimination between malignant and non malignant tumours. This confirms earlier findings that RBC polyamines are markers of the cell proliferation rate, but not for the presence of a malignant tumour. Elevated RBC polyamine concentrations are an index of the intensity of hyperplastic processes, which can be clinically used for the early detection of proliferative phases of tumours, thus allowing timely therapeutic measures.

Animals↗

PubMedDate not supplied

Accumulation of hydroxyspermidine in red blood cells, a potential index of tumor proliferation rate.

It has previously been demonstrated that during Lewis Lung carcinoma growth, red blood cell spermidine levels increase concomitantly with tumor volume. If [14C] putrescine or 2-methylputrescine are administered, [14C] spermidine and methylspermidine, respectively, accumulate in red blood cells in proportion with the tumor volume. In the present work the metabolic transformation of 2-hydroxyputrescine, a natural derivative of putrescine, to hydroxyspermidine, was studied in tumor bearing mice. After a single i.p. injection of 2-hydroxyputrescine, higher concentrations of hydroxyspermidine were found in the tumor than in liver. In the red blood cells of Lewis lung carcinoma-bearing mice, hydroxyspermidine was detected between 24 hours and 96 hours after i.p. injection of 2-hydroxyputrescine. The concentration of hydroxyspermidine found in red blood cells was proportional to the tumor volume. Hydroxyspermidine has potential as a marker of malignant cell proliferation in human oncology.

Animals↗