Red blood cell polyamines, anaemia and tumour growth in the rat.

In rats with Mat Lylu prostatic carcinoma, significant changes in blood composition and red blood cell (RBC) characteristics were observed. Anaemia, characterised by a decrease in the number of RBC and the reduction of haemoglobin and the iron content in plasma, was correlated with tumour size and the accumulation of spermidine and spermine in the RBC. In large tumours, spermidine levels were increased by 8-fold over normal value. Spleen weight and splenic spermidine concentrations were enhanced in animals with tumours. After splenectomy, the rate of tumour growth decreased by 30%. It is proposed that anaemia in tumour-bearing animals is caused by enhanced RBC lysis, owing to the alteration of the rheological properties of RBC. These may be caused by the alterated surface characteristics due to polyamine accumulation. RBC lysis and high concentrations of polyamines in RBC and spleen appear, not only to favour tumour growth, but also to compromise the immunological defence mechanisms against neoplastic invasion.

Polyamine deprivation alters formalin-induced hyperalgesia and decreases morphine efficacy.

Although the exact functions of polyamines in the nervous system remain still unclear, they are thought to have a physiological role in intracellular signal processing and neurotransmission. Polyamine deprivation which consists in the reduction of both the endogenous and exogenous sources of polyamines is a promising treatment for cancer. In a previous study we have shown that this treatment provokes an analgesic effect in rats submitted to brief phasic nociceptive tests. The present study examined the effect of polyamine deprivation on pain-related behaviors and spinal c-fos expression evoked in the formalin test presumed to better reflect clinical pain, using morphine as analgesia control. Polyamine deprivation per se altered the characteristic pain-related behaviors, reducing the interphase depression of pain, without inducing changes in the spinal Fos staining. In addition this treatment prevented the antinociceptive effect of morphine both on behavioral responses and on spinal c-fos expression. In polyamine-deprived rats, despite morphine injection, nociceptive scores remained dramatically high during the intermediate and the late phases of the response and the number of Fos immunoreactive neurons remained largely higher in deeper layers than in morphine control rats. Altogether these data support a modulatory role of polyamines both on the neuronal circuitry mediating sensory information, and on mechanisms underlying morphine analgesia.

Benefits of complete polyamine deprivation in hormone responsive and hormone resistant MCF-7 human breast adenocarcinoma in vivo.

Polyamines are ubiquitous cellular compounds which are required for estradiol induced proliferation in breast cancer. Complete polyamine deprivation, using 2 alpha-difluoromethyl-ornithine (DFMO, Eflornithine), a specific inactivator of ornithine decarboxylase (key-enzyme of the polyamine biosynthesis) combined with inhibition of the bacterial production of gastrointestinal polyamine and a polyamine free regimen, was demonstrated to exhibit a cytostatic effect and a decrease of the three tumoral polyamine concentrations in a MCF-7 tumor model. In this experiment, complete polyamine deprivation has been tested on a standard MCF-7 tumor and on a variant MCF-7 tumor (i.e. with a tamoxifen acquired resistance). Polyamine deprivation was effective on the tumor growth, both on standard and variant sub-types. The polyamine contents of two types of tumor were similar, and identically, polyamine deprivation has caused a decrease of putrescine, spermidine and also spermine tumoral concentrations measured by the HPLC method in standard and variant MCF-7 tumors. Acquired tamoxifen resistance is common in patients undergoing hormonal therapy for advanced breast cancer. It has been hypothesized that the direct stimulation of polyamine pathway without estradiol involvement could be one of the mechanisms responsible for the tamoxifen resistance. The ability of polyamine deprivation to inhibit the growth of tumors becoming tamoxifen resistant could offer a therapeutic advantage in case of tumor with acquired tamoxifen resistance and could be tested to prevent or delay the hormonal responsiveness to breast cancer.

Polyamine deprivation prevents the development of tumour-induced immune suppression.

Mice grafted with the 3LL (Lewis lung) carcinoma exhibit immune suppression: spleen cells showed decreased spontaneous interleukin 2 (IL-2) production and T-CD4+ and T-CD8+ lymphocyte populations; in addition the polyamine content in the spleen was increased. By treating the mice with a polyamine-deficient diet containing neomycin, metronidazole and inhibitors of ornithine decarboxylase and polyamine oxydase, tumour growth was reduced and the immune abnormalities were reversed. The spleen cells overproduced IL-2 by reducing exogenous sources of polyamines, but total blockade of all major polyamine sources was necessary to obtain an optimal effect both on IL-2 production and on spleen polyamine content. Irrespective of whether polyamine deprivation was started at an early or at an advanced stage of tumour growth, T-lymphocyte populations were restored to normal values, demonstrating that polyamine deprivation not only prevents tumour-induced immune suppression, but reverses established immunological disorders. In contrast to what was observed regarding IL-2 production by spleen cells and natural killer (NK) cell activity, the polyamine oxidase (PAO) inhibitor did not enhance the number of T lymphocytes. These findings are consistent with a direct effect of the polyamines on immune effector cell metabolism. They suggest an important role of the gastrointestinal polyamines and of PAO activity in the regulation of IL-2 production.