Biomedicine & Pharmacotherapy

The sensitivity of stromal progenitor cells (CFU-F) in mouse marrow to whole-body 60Co gamma-irradiation delivered at 0.65 Gy per day, was characterised by a D0 value of about 2.5 Gy up to an accumulated dose of 5 Gy. The cells were less sensitive to higher doses. The rate of recovery following irradiation for 14 days (9.1 Gy) was less than the rate after 30 days irradiation (19.5 Gy). The latter rate of recovery approached that of the stem cells (CFU-S). At 9-10 months after either dose of irradiation, recovery of both CFU-F and CFU-S was incomplete at 30-70% of the aged control.

NOV-002 is a novel therapeutic agent in development for oncology indications used in combination with chemotherapy. Clinical trials in Russia and the USA have demonstrated clinical activity and the present focus is on non-small cell lung cancer (NSCLC) patients. The active component of the drug is oxidized glutathione (GSSG) and this imparts multiple effects upon redox pathways both at the cell surface and inside the cell. The drug induces S-glutathionylation of some proteins and impacts kinase/phosphatase regulated signaling pathways. Induction of myeloproliferation is believed to contribute to the clinical advantages provided by NOV-002 that include improved tolerance of chemotherapy and increased survival.

NOV-002 is a glutathione disulfide (GSSG) mimetic that is the subject of clinical investigation in oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Non-linear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of approximately 13 min with an AUC of 1.18 μgh/mL, a C(max) of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis.

NOV-002 is a glutathione disulfide (GSSG) mimetic with chemoprotective activity. Previous and ongoing clinical studies demonstrate a significantly improved 1-year survival and decreased tumor progression rates in non-small cell lung (NSCLC) and ovarian cancer patients when NOV-002 was included in cisplatin containing regimens. In order to understand this chemoprotective property, we employed as an animal model of kidney toxicity, 8-week-old Bl6 mice that were treated with a single nephrotoxic dose of cisplatin (15 mg/kg, ip) and sacrificed on Day 5. One group of animals was treated with NOV-002 (15 mg/kg, im) daily. NOV-002-treated mice had significantly lower levels of plasma creatinine compared to mice treated with cisplatin alone (4.7 vs 2.9 mg/dL, respectively). Moreover, NOV-002 protected the kidneys from cisplatin mediated proximal tubule damage, including dilation of tubules and the presence of protein casts. Since cisplatin-induced nephrotoxicity can be mediated by a glutathione-platinum conjugate catalyzed by gamma-glutamyl-transpeptidase (GGT) and glutathione is an endogenous substrate of GGT, the protective effect of NOV-002 in the kidney may be attributed to its ability to act as a competitive substrate for the enzyme.

Polyamine biosynthesis and inhibition in parasites have been an attractive chemotherapeutic approach in the design of novel antiparasitic drugs. We study in this work the effect of N-dodecyl-1,2-ethylenediamine (NDDE) on the morphology and replication of Leishmania using macrophages cultured from the peritoneal exudate of mice infected in vitro with three species of Leishmania: Leishmania (Leishmania) amazonensis, Leishmania (Viannia) brasiliensis and Leishmania (Leishmania) chagasi. The results showed that NDDE inhibited Leishmania amastigotes multiplication into inflammatory peritoneal cells in concentrations which were not toxic to mammalian cells (0.5-1μg/mL). An intracellular disorganization of the promastigote forms was observed by transmission electron microscopy after 3 to 24h of treatment with 1μg/mL NDDE, suggesting that this compound affects the viability of the parasite by an autophagy pathway.

Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane) platinum (II) (l-OHP), was studied. This water-soluble platinum complex showed a more prominent life-prolonging effect on a mouse leukemia L1210 than cisplatin (DDP). By an intermittent treatment schedule cured mice were observed at the optimal dose. In addition, a subline of L1210 having a 40-fold resistance to DDP (L1210/DDP) showed lack of cross-resistance to l-OHP both in vivo and in vitro. Especially in vivo l-OHP was more active against L1210/DDP than against the original L1210, and all mice were cured at doses of 6.25 and 3.12 mg/kg. l-OHP was also effective against several mouse tumors such as P388 leukemia, B16 melanoma, Lewis lung carcinoma, colon 26 and colon 38 adenocarcinomas, and M5076 fibrosarcoma, though its antitumor spectrum was somewhat different from that of DDP. The synthesis of both DNA and RNA in L1210 cells was inhibited by about 50% with exposure to 10 microM of l-OHP for 1 h, followed by postincubation in drug-free medium for 6-24 h, while only the inhibition of DNA synthesis was observed by DDP in the same experiment. If severe toxicity is not observed in preclinical study, l-OHP expected to be a new clinically active Pt complex.

Studies in our laboratories have led to the discovery of the delta 2-1,2,3-triazolines as a unique family of anticonvulsant agents hitherto unknown. The anticonvulsant activity of 1,5-diaryl- and 1-aryl-5-pyridyltriazolines was previously reported; this paper describes the evaluation of two series of 1-aryl-5-amido-1,2,3-triazolines, A and B, where the 5-amido groups are (2-oxo-1-pyrrolidino)- (1-8) and (N-methyl-N-acetamido)- (9-15), respectively. The 1-aryl-5-(2-oxo-1-pyrrolidino)-1,2,3-triazolines of the A series, which are uniquely substituted with the pyrrolidinone lactam ring, a cyclic gamma-aminobutyric acid (GABA) structure, seem to function by enhancing inhibitory GABAergic mechanisms. Radioligand binding studies for the two most active triazolines 2 and 7, indicate that both compounds strongly inhibit the specific binding of [3H]GABA to GABAB receptor sites, with Ki = 1.7 and 0.91 microM respectively. The anticonvulsant activity among the various groups of triazolines studied so far appears to be dependent on the 5-substituent groups: 4-pyridyl- > 2-oxo-1-pyrrolidino- > N-methyl-N-acetamido- > 3-pyridyl > or = aryl approximately 2-pyridyl > 2-quinolyl.

A series of novel 4-butyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones were synthesized by the cyclization of 3-butyl-2-hydrazino-3H-quinazolin-4-one with various one carbon donors. The starting material 3-butyl-2-hydrazino-3H-quinazolin-4-one was synthesized from butyl amine by a new innovative route. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. Compound 4-butyl-1-methyl-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-one (II) emerged as the most active compound of the series and it is equipotent (71.91% protection) when compared to the reference standard chlorpheniramine maleate (71% protection). Compound II show negligible sedation (9%) when compared to chlorpheniramine maleate (30%).

A new series of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one were synthesized to study the effect of cyclization of the semicarbazone moiety of aryl semicarbazones on the anticonvulsant activity. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity in four animal models of seizures, viz. maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. The compounds were also evaluated for neurotoxicity. Compounds 4, 9, 14-19 exhibited anticonvulsant activity in all the four animal models of seizure.

Forty-four patients with high risk primary myelodysplastic syndromes and an excess of marrow blasts were treated with a combination of low-dose Ara-C, retinoic acid and vitamin D3. Morphological subtypes were refractory anemia with excess of blasts (RAEB) in 16, RAEB in transformation (RAEB-T) in 20 and chronic myelomonocytic leukemia (CMML) in eight patients. The therapy was continued in responders until relapse or death. The results were compared to those of a matched control of 44 patients given a supportive therapy only. In the treated group the overall response rate was 50% (75% in RAEB, 50% in RAEB-T and 0% in CMML) and the survival was significantly better than in the control group (P < 0.025). Comparing separately each FAB subgroup gave statistical evidence that the treatment prolonged the survival in the RAEB-T subgroup only (P < 0.002). The median duration of response was 15 months and the survival in responders was statistically better than in non-responders (P < 0.0001). Myelosuppression has been the most important side effect, however, no death related to the treatment was observed. Our study suggests that patients with RAEB-T, who are not suitable candidates for aggressive chemotherapy, could benefit from our treatment schedule. The long duration of therapy seems to be of value for patients achieving a response in order to prolong the survival. The toxicity is acceptable and the therapy can be given on an outpatient basis.

Treatment of the human promyelocytic leukaemia cell line HL-60 with 1,25(OH)2D3, the active metabolite of vitamin D3, led to a dose- and time-dependent inhibition of growth and 3H-TdR incorporation at the population level. A similar effect was noted at the single cell level in clonogenic assays and autoradiographic experiments. Flow cytometry indicated that there was an arrest of cells in the G0/G1 phase of the cell cycle. Parallel to the loss of proliferative capacity 1,25(OH)2D3 induced differentiation of HL-60 into monocyte/macrophages as measured by the enzyme NSE and the macrophage membrane antigen recognised by the monoclonal antibody EB11 as well as by morphological changes. These findings reinforce the concept of concordant induction of differentiation and loss of proliferative capacity and demonstrate that the latter occurs not only at the population level but also at the single cell level in this system. In limiting dilution assays in liquid culture there was evidence for positive interactions between HL-60 cells as untreated cells gave less colonies at low dilutions than would have been expected by Poisson statistical analysis. In the presence of 10(-8) M 1,25(OH)2D3 more complex growth parameters were noted indicating the involvement of both positive and negative cellular interactions.

QA1 and QA3 are the derivatives of substituted 1,3-dimethyl-1H-quinoxalin-2-ones that may selectively antagonize P-glycoprotein (P-gp) in multidrug resistance (MDR) cancer cells. Herein, we examined the reversal effect of two compounds on MDR in adriamycin (Adr)-induced resistant K562/A02 cells. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay showed that QA1 and QA3 weakly inhibited the growth of tumor cells. However, the compounds increased Adr-induced cytotoxicity toward K562/A02 cells. The IC(50) values of Adr toward K562/A02 were decreased in the presence of QA1 or QA3. The maximal reversal fold (RF) of QA1 and QA3 was reached 6.9 and 9.0, respectively. The action of QA1 and QA3 was also confirmed by the increase of intracellular Adr accumulation in K562/A02 cells. In mechanism study, the intracellular accumulation and efflux of Rh123 were measured using multilabel counter with excitation/emission wavelengths of 485/535nm. An increase of intracellular Rh123 and the decrease of efflux were observed in K562/A02 cells incubation with QA1 or QA3, indicating that the activity of P-gp was blocked. These results suggested that the derivatives of substituted 1,3-dimethyl-1H-quinoxalin-2-ones might reverse MDR in K562/A02 cells via inhibition activity of P-gp. QA1 and QA3 might be the candidate agents for reversing MDR of cancer.

Glucans have a long history as non-specific biological modulators; however, but the search for optimal chemical configuration is still on. The objective of this study was to evaluate intraperitoneal application of PS3, a sulfated derivative of a (1-->3)-beta-D-glucan isolated from sporophytes of Laminaria digitata. PS3 showed significant stimulation of phagocytic activity as well as potentiation of synthesis and release of IL-2 by splenocytes. In addition, PS3 increased NK cell-mediated killing of tumor cells both in vitro and in vivo. When combined, our observations suggest that PS3 is similarly effective as native non-sulfated (1-->3)-beta-D-glucan and is generally more active than lentinan.

Sixteen patients with type 2 diabetes poorly controlled by glibenclamide (7.5-10.0 mg/day) were treated with acarbose (100 mg tds) for one week and the effect on the blood glucose profile, 24-hour urinary glucose excretion, plasma fructosamine, and plasma 1,5-anhydro-D-glucitol (1,5-AG) level was determined. The blood glucose profile was more stable and levels were lower during acarbose administration. In some patients, this improvement was maintained after discontinuing acarbose. The M-value, an indicator of blood glucose fluctuations, decreased significantly from 33.2 +/- 3.0 (mean +/- SEM) in the run-in period to 13.4 +/- 2.4 during acarbose therapy (P < 0.001), and rose again to 26.5 +/- 4.4 (P < 0.001) in the follow-up period. The 24-hour urinary glucose excretion and plasma fructosamine decreased similarly (P < 0.001 and P < 0.01, respectively) during and after acarbose therapy. Plasma 1,5-AG levels did not change significantly during acarbose therapy, but increased markedly afterwards (from 19.3 +/- 3.1 mumol 1(-1) to 25.0) +/- 3.1 mumol l-1, P < 0.001). Plasma 1,5-AG levels were significantly correlated with urinary glucose excretion one week earlier (r = 0.513, P < 0.006). These findings suggest that acarbose may improve glycemic control in type 2 diabetic patients poorly controlled by sulfonylurea therapy and that plasma 1,5-AG might be used as a marker of glycemic control cooperating with other markers such as fructosamine and urinary glucose determination for monitoring the short-term response to antidiabetic therapy.

We studied the effect of synthetic ajoene on simian immunodeficiency virus (SIVagm)-mediated cell fusion and subsequent virus-induced cytolysis. Our data indicate that this compound is a strong antifusion agent with a 50% syncytium inhibitory concentration (SIC50%) value of about 2.9 microM. We suggest that ajoene interacts with the cell-specific integrin molecules and sterically hinders the association between fusion (or other co-receptors) and the CD4-gp120 complex at the cell surface of SIV-infected cells. Although ajoene was maximally effective in suppressing syncytium formation during the early period (ie, up to 6 h) of the fusion process, when the compound was recurrently added to the co-cultures, the inhibitory effect was regained and further cell death was markedly delayed. This indicates that ajoene was also effective after the initial cell-to-cell contact stage. These data suggest that ajoene may be a promising approach for the treatment of SIV/human immunodeficiency virus (HIV) infections.

Studies were performed to establish whether synthetic ajoene exhibited differential inhibitory activity against human immunodeficiency virus (HIV)-1 (IIIB) and to clarify the mechanism of its antiviral effects. Our results demonstrate that ajoene protected acutely infected Molt-4 cells against HIV-1 and blocked further destruction of CD4 T-cells in vitro. Ajoene showed dose-dependent inhibition, with 50% cytotoxic concentration (CTC50%) and 50% effective inhibitory concentration (EIC50%) values of 1.88 microM and about 0.35 microM, respectively, when the test compound was added before or after HIV-1 infection and incubation carried out at 37 degrees C for 4 days. Ajoene proved relatively more active than dextran sulfate in blocking HIV-1 virus-cell attachment. The mode of anti-HIV action of ajoene can be ascribed to the inhibition of early events of viral replication, particularly virus adsorption.

Self-experimentation concerns not only scientists, but also each individual for the sake of his/her chronobiologic health and science literacy, eventually to be acquired in primary and secondary education. Public education ensures that everybody who knows how to read or write can dispense with the service of a costly scribe. At all ages, public education can teach equally well how to find out whether one's blood pressure (BP) and heart rate (HR) responds to an increase in sodium intake with a rise, with no change or with a decrease in BP. This task and many others could become a matter of informed self-surveillance. Whenever there are inter-individual, sometimes opposite differences in response, government-sponsored trials on groups that do not consider such differences cannot solve what only the individual can do, at first by help from schools. Eventually special institutions may be designed for chronomics, the monitoring, interpretation and archivization of chronomes (time structures; from chronos = time and nomos = rule) of biological variables, also charged with a demographic analyzing and reporting system. Each individual's properly coded record, to guard confidentiality, becomes part of a promptly accessible database for one's own needs and for society's requirements. What individuals and small groups started as chronobiology, what is immediately available on back burners, as a service by an international project on the biosphere and the cosmos (BIOCOS) ([email protected] /* */) could become a public system of planned surveillance archivization of one's rhythms from womb to tomb. Alterations of a rhythm's amplitude or acrophase or of a deterministic or other chaotic endpoint, such as a correlation dimension and approximate entropy, or of a standard deviation, among a multitude of other endpoints, can signal (in the otherwise neglected normal range) reversible risk elevations. If these elevated risks are detected and prompt the institution of countermeasures, such prehabilitation can save the cost of rehabilitation or of long-term care after morbid events; suffering also can be prevented such as that by those who are unlucky enough to helplessly survive a massive brain, heart or societal "stroke". As an equally important dividend, science gains in basic and applied terms, as illustrated herein by the demonstration of a trans-year, an ∼1.3 to 1.6-year, heretofore unknown component of the human BP and HR spectrum, beating with the circannual component and characterizing the same data. Chronomically interpreted self-monitoring is a civic duty for both one's health and everybody's science. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

Acute toxicity to the hematopoietic cell renewal system is a critical side effect of most anticancer agents. Here we compared the effects of FAD-104 to those of the parent compound adriamycin (ADM) and of epi-adriamycin (epi-ADM) on the growth and differentiation of normal as well as leukemic human myeloid progenitor cells. FAD-104 was less toxic to myeloid colony-forming cells (GM-CFU) than ADM or epi-ADM. In addition, FAD-104 but not ADM induced a clonal down-grading in both normal and leukemic blast cells, and it stimulated the terminal differentiation of myeloid leukemia cells. Therefore, FAD-104 may be useful in the treatment of some forms of myeloid leukemia.

We examine whether autism may be influenced by non-photic environmental factors, among others, in a California database consisting of the number of cases added quarterly to the system between 1993 and 2004. Instead of a precise calendar (1.0)-year-long spectral component, we detect unseen primarily helio- and geomagnetic signatures, including a newly discovered near-transyear of 1.09-year length. In this case, it overrides any undetected seasonal effects, the topic of much previous unrewarding research, also analyzed herein without overcoming the limitation by stacking. Since we could not get additional data on autism, data on suicides, the final "detachment" and failure to bond, were also analyzed, again revealing a spectrum of non-photic signatures. What we do not see and do not anticipate can exist and can override the seasons, as resolved time-microscopically by chronomics, the study of chronomes (time structures). Just as spatial microscopy and electron microscopy resolved infectious agents, so does microscopy in time resolve the signature of environmental agents in human behavior in health and disease.

Synergistic effect of polyoxometalates, K(6)[P(2)W(18)O(62)].14H(2)O (P(2)W(18)), K(4)[SiMo(12)O(40)].3H(2)O (SiMo(12)), K(7)[PTi(2)W(10)O(40)].6H(2)O (PTi(2)W(10)), and K(9)H(5)[alpha-Ge(2)Ti(6)W(18)O(77)].16H(2)O (Ge(2)Ti(6)W(18)), in combination with a beta-lactam oxacillin against methicillin-resistant and vancomycin-resistant Staphylococcus aureus (characterized by possessing the penicillin-binding protein 2' (PBP2') as a cell-wall synthesis enzyme) with a high initial inoculum of 1 x 10(8) cfu/ml (for in vivo test) was investigated with a help of the growth curve and the reverse transcription polymerase chain reaction (RT-PCR) analyses. The growth curves showing the suppression of cell proliferation of the strains based on the synergistic effect of the polyoxometalates in combination with oxacillin indicated a recovery of the cell proliferation during continuous cultivation. The duration of the suppression of the cell proliferation increased with increasing the concentration of the polyoxometalates, depending on the amounts of the initial inoculum of the strain. The RT-PCR results for P(2)W(18), SiMo(12), and PTi(2)W(10) indicated the suppression of expression of the PBP2'-encoding mecA gene in contrast to the ones for Ge(2)Ti(6)W(18). The difference in the RT-PCR results among the polyoxometalates suggests that there remain other factors for the inhibition of PBP2' production such as post-transcription process.

Cell destruction in boron neutron capture therapy is effected by nuclear reaction between 10B and thermal neutrons with the release of alpha-particles (4He) and lithium-7 ions (7Li). 4He kills cells within 10 microm of the site of 4He generation, therefore it is theoretically possible to destroy tumour cells without affecting adjacent healthy tissue, given selective delivery of compounds containing 10B. Liposomes wore prepared by vortex dispersion of solutions containing 10B compounds with dried lipid films and the effects of those compounds on human breast cancer cells in culture were examined after thermal neutral irradiation. [3H]-TdR incorporation by MRKnu/nu-1 cells treated with 10B-containing liposomes showed 40% suppression compared with liposomes without 10B, at 2 x 1012 n/cm2 thermal neutron fluence. Inhibition of tumour cell growth with liposomes prepared with 100 mm 10B-compound was as significant as with those made with 500 ppm 10B solution. The concentration of 10B in liposomes was 76.5 +/- 3.4 microg/mL. Boronated liposomes can thus deliver sufficient 10B atoms to this line of breast cancer cells in culture to effect cytotoxicity and suppression of growth after thermal neutron irradiation.

Collateral drug sensitivity was induced in CPT-11-resistant cell lines (CPT-K and T). Ten of the 19 kinds of antineoplastic agents (especially, 5 of 6 kinds of DNA topoisomerase n inhibiting agents) were effective in inducing collateral drug sensitivity. Alteration of DNA topoisomerase I seemed to be unrelated to acquisition of multidrug resistance. Résumé: Sensibilité collatérale aux médicaments induite dans des lignées cellulaires résistantes à la CPT-11 (un nouveau dérivé de la camptothécine). Une sensibilité collatérale aux médicaments a été induite dans des lignées cellulaires résistantes à la CPT-11 (lignées CPT-K et T). Parmi les 19 sortes d'agents antinéoplasiques, 10 ont été efficaces dam l'induction de cette sensibilité collatérale. Il s'agissait en particulier de 5 à 6 agents inhibiteurs de la topoïsomérase II de l'ADN, Les altérations de la topoïsomérase l de l'ADN semblent sans relation avec l'acquisition d'une multirésistance aux médicaments.

We have performed pituitary scintigraphy with 111In-pentreotide (OCT), a somatostatin analogue, and with metoxybenzamide (IBZM) by 123I- IBZM in two patients affected by mixed growth hormone/prolactin-secreting pituitary tumors. Short-term growth hormone (GH) inhibition by a single injection of OCT (100 μg sc), and short-term prolactin (PRL) inhibition by oral administration of 2.5 mg of bromocriptine (BCR), were also performed in both patients. The first patient, a 26 year old man, showed intense tumor uptake of 123I-IBZM scintigraphy, whereas 111In-OCT scintigraphy showed moderate tumor uptake. Five hours after the BCR inhibition test, a fall of 83% in PRL plasma levels (from 8,336 μg/L to 1,417 μg/L), and of 91.6% in GH plasma levels (from 39.5 μg/L to 3.3 μg/L) were observed. OCT inhibition test suppressed GH plasma levels from 36 μg/L to 3.5 μg/L. The patient was submitted to treatment with BCR and OCT. A dramatic shrinkage of the tumor was seen after six months of therapy. The lesion disappeared one year after the start of therapy. The second patient, a 64 year old man, showed intense uptake at 111In-OCT scintigraphy, while 123I-IBZM uptake was not observed. A test dose of BCR resulted in an acute fall of PRL (from 145 μg/L to 118 μg/L), but not of GH. A test dose of OCT decreased the GH plasma level from 61 μg/L to 4.5 μg/L. The patient was submitted to treatment with BCR and OCT that resulted in a computed tomography and magnetic resonance imaging decrease of 45% of tumor volume one year after the start of therapy. Our results suggest that both suppression tests with OCT and BCR, and scintigraphic studies in vivo with 123I-IBZM and 111In-OCT can be predictive for the effectiveness of therapies with dopamine agonists and/or SS-analogs in patients with mixed PRL/GH-secreting pituitary tumors. Further studies are required to evaluate the role of suppressive tests in selecting patients for appropriate clinical treatments.