Biomedical subjects

R Havouis

Publications and source records attributed to R Havouis.

44 records · Page 3Linked to original sources

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

[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

Polyamine content and oncogene expression in hepatoma cells in culture during methionine deprivation and refeeding.

From an hepatocarcinoma cell line (LFCL.2A), unable to grow in a culture medium in which methionine was replaced by L-homocysteine, we had previously isolated revertant clones presenting a low growth rate, a loss of tumorigenicity and an inhibition of transcription of three oncogenes: c-Ki-ras, c-Ha-ras and c-myc. Here we showed that long-term deprivation of methionine led to a depletion of spermine, while putrescine and spermidine contents remained unchanged. When the revertant cells were shifted in a medium containing methionine, the oncogene transcription (except the p53 gene) started very rapidly in parallel with an increase in the putrescine content. By contrast, spermidine and spermine contents decreased during the first hours but were not significantly different from control values after numerous subcultures in methionine-containing medium.

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↗

PubMedDate not supplied

The gastrointestinal polyamine source depletion enhances DFMO induced polyamine depletion in MCF-7 human breast cancer cells in vivo.

Due to the polyamine requirement for cell growth, blockade of polyamine biosynthesis is considered a potential anticancer target. The lack of efficacy of DFMO in vivo, has been attributed to other sources of polyamines, mainly from the gastrointestinal tract (alimentary and bacterial). An experiment was designed to test the role of intestinal polyamine deletion in addition to DFMO (a specific inhibitor of ODC) in established MCF-7 tumors in nude mice. Using DFMO and polyamine-free diet, the tumor putrescine concentrations were more profoundly decreased in comparison to DFMO alone and cellular spermine was also depleted, as has never been observed with DFMO alone. The blockade of the gastrointestinal sources of polyamines enhances the intracellular polyamine depletion induced by DFMO on MCF-7 tumor in nude mice.

Animals↗