Biomedical subjects

G R Rutteman

Publications and source records attributed to G R Rutteman.

At least 73 records · Page 4Linked to original sources

PubMed1988

[Chemotherapy of tumors in dogs].

The general principles of chemotherapy in oncology and the various types of antineoplastic drugs are discussed. Particular attention was paid to the results of chemotherapy in dogs and cats as reported in the literature. Chemotherapy is indicated in neoplastic disease characterised by early metastasis and/or local invasive growth. The results of chemotherapy in dogs and cats are so far moderate. Chemotherapy studies in the Netherlands are discussed: predictive in vitro, PEG-asparaginase studies in canine lymphosarcoma and regional perfusion in canine osteosarcoma.

Animals↗

PubMed1988

Mitogenic stimulation of human breast cancer cells in a growth factor-defined medium: synergistic action of insulin and estrogen.

The cooperative action of 17 beta-estradiol (E2) and polypeptide growth factors in stimulating proliferation of human breast cancer cells in vitro was investigated. To prevent background estrogenic stimulation, only phenol red-free media were used. When cultured in media supplemented with steroid-stripped serum in which all polypeptide growth factor activity had been chemically inactivated, MCF7 cells were unable to proliferate and became virtually quiescent. In the additional presence of insulin, epidermal growth factor (EGF), and E2, however, cells proliferated as rapidly as did cells cultured in media supplemented with fetal calf serum. Analysis by DNA flow cytometry showed that in the absence of external growth factors, MCF7 cells became arrested predominantly in the G1/G0 phase of the cell cycle. Upon addition of insulin in combination with EGF and E2, however, cells reentered the cell cycle with a high degree of synchrony. When added alone, E2 induced only slight mitogenic effects under these growth factor-defined conditions. In contrast, this steroid induced optimal proliferation in conventional steroid-stripped serum, which in itself contained considerable mitogenic activity. Insulin (at 10 micrograms/ml) was the most potent stimulator of MCF7 cell proliferation under growth factor-defined conditions, resulting in a more than sixfold increase in cell number after 96 hours. Other growth factors such as platelet-derived growth factor (PDGF), transforming growth factor beta (TGF beta), and EGF had little effect by themselves and only slightly influenced insulin-induced proliferation. At suboptimal concentrations of insulin (10-100 ng/ml), however, strong synergism was observed between E2 and insulin in inducing MCF7 proliferation. Using the CG5 cell line, a highly E2-sensitive MCF7 variant, synergism with E2 was already observed at 1 ng/ml insulin. It is concluded that MCF7 cells require insulin (or insulin-like growth factors) for proliferation. At suboptimal insulin concentrations, E2 acts synergistically with insulin, possibly by inducing autocrine production of polypeptide growth factors by these cells.

Animals↗

PubMed1988

Oestrogen (ER) and progestin receptors (PR) in mammary tissue of the female dog: different receptor profile in non-malignant and malignant states.

Oestrogen (ER) and progestin receptors (PR) were measured in cytosols from histologically normal mammary tissues (n = 30), and in benign (n = 59) and malignant mammary lesions (n = 49) from female dogs. Receptor levels greater than or equal to 5 fmol mg-1 protein were considered positive. The presence of histologically normal mammary epithelium within specimens of primary tumours was noticed as a factor that may cause false-positive receptor results. Receptor levels in non-malignant tissues, and the receptor status of primary cancers did not vary significantly with regard to the phase of oestrous cycle (anoestrus/metoestrus) or the influence of exogenous progestins. ER- or PR-positivity was more frequent and levels of both receptors were higher in 'normal' tissues and in benign lesions than in primary cancers (P less than 0.001). ER and PR levels were higher in benign lesions of dogs also developing malignant mammary tumours than in benign lesions of dogs that did not (P less than 0.02 and P less than 0.05, respectively). Regional and distant cancer metastases were frequently receptor-negative. In some dogs heterogeneity of receptor status was found between different sites of the same cancer. These findings indicate that in non-malignant mammary tissues of adult female dogs expression of the genes encoding ER and PR is common. In malignant tumours this property may become lost, in particular in advanced states of disease.

Animals↗

PubMed1987

Medroxy-progesterone acetate administration to ovariohysterectomized, oestradiol-primed beagle bitches. Effect on secretion of growth hormone, prolactin and cortisol.

Growth hormone (GH), prolactin (Prl) and cortisol secretion was studied in 5 ovariohysterectomized dogs before and after oestradiol implantation and medroxyprogesterone acetate (MPA) administration. MPA was given at regular intervals during a period of 10 months in a total of 12 injections. Short-term effects of oestradiol were restricted to significantly enhanced Prl responses to thyrotropin-releasing hormone (TRH). MPA treatment after oestradiol implantation resulted in significantly elevated basal GH levels in all dogs, with a continuing increase in one dog. Only in the latter dog was a significant decrease in basal Prl levels seen. MPA administration did not significantly change Prl responses to TRH. The GH responses to clonidine were significantly reduced at 9 and 16 weeks of oestradiol and MPA treatment. In the one dog which exhibited the greatest rise in basal GH levels, GH responses were completely abolished at 9, 16 and 43 weeks of oestradiol and MPA treatment. TRH never evoked significant GH responses. Both basal and lysine-vasopressin (LVP)-stimulated cortisol levels were significantly suppressed during combined oestradiol-MPA treatment. These findings denote that in the dog. Oestradiol rapidly induces an enhanced Prl response to TRH. The oestradiol-MPA induced GH overproduction is associated with a reduced responsiveness of GH to clonidine and is not accompanied by GH responsiveness to TRH. Oestradiol-MPA treatment suppresses both basal and LVP-stimulated cortisol secretion.

Animals↗

PubMed1987

C-reactive protein in dogs.

Serum concentrations of C-reactive protein (CRP) in dogs with various diseases or undergoing various procedures were measured by specific immunoassay. In 20 healthy dogs from various sources, values were all less than 5 mg/L, but in 22 healthy dogs from a single source, values ranged from less than 5 mg/L in 14 dogs and from 8 to 67 mg/L in 8 dogs. Increased concentrations of serum CRP were attained 24 hours after injection of casein (n = 9; median 188 mg/L), ovariohysterectomy (n = 11; median, 144 mg/L), or elective, nonacute orthopedic surgery (n = 10; median, 83 mg/L). After inoculation of Leptospira interrogans serovar canicola (n = 5), the behavior of serum CRP as an acute-phase reactant provided a sensitive and precise objective reflection of in vivo response. The CRP concentration in random single-serum samples from 73 dogs with other inflammatory and noninflammatory disorders ranged from normal (less than 5 mg/L) to 246 mg/L and generally correlated with the extent and activity of disease.

Animals↗

PubMed1986

Regulation of prolactin secretion in canine pituitary-dependent hyperadrenocorticism.

In 15 dogs with pituitary-dependent hyperadrenocorticism (PDH) the basal prolactin concentrations (means of 6 determinations; range 2.8-24.7 micrograms/l) were significantly higher than those of 23 healthy control dogs (0.9-10.5 micrograms/l). In five dogs with hyperadrenocorticism due to adrenocortical tumour (ATH) the prolactin concentrations were also significantly elevated, but still significantly lower than the values of the dogs with PDH. The prolactin concentrations of the dogs with PDH responded supranormally to TRH-stimulation, whereas in the dogs with ATH the response was not significantly different from the results in the control dogs. Following bromocriptine administration the plasma prolactin concentrations of the dogs with PDH decreased considerably but remained higher than the values obtained in the control dogs and the dogs with ATH. It is concluded that PDH in the dog is associated with a disturbance in the regulation of prolactin secretion, that is not secondary to hypercortisolism per se.

Adrenal Cortex Diseases↗

PubMedDate not supplied

Relation between habitual diet and canine mammary tumors in a case-control study.

In the present case-control study several dietary and nutritional factors were investigated to determine if a relationship exists between diet and development of mammary tumors in female dogs. Control female dogs (n = 86) were compared with a case group of dogs (n = 102) with dysplasias or tumors of the mammary gland. A questionnaire providing information on the dog's body conformation and dietary and reproductive histories was answered by the owners. Serum selenium and retinol concentrations and the fatty acid profile in subcutaneous adipose tissue were analyzed as indicators of nutritional status. Obesity at 1 year of age and 1 year before the diagnosis of mammary nodules was found to be significantly related to a higher prevalence of mammary tumors and dysplasias. The intake of homemade meals (compared to that of commercial foods) was also significantly related to a higher incidence of tumors and dysplasias. Other significant risk factors were a high intake of red meat, especially beef and pork, and a low intake of chicken. The subcutaneous fatty acid profile and the serum selenium concentration were not significantly different in the cases and the controls, with the exception of C18:1 fatty acid (oleic acid) content, which was significantly higher in the cases than in healthy controls. Serum retinol concentration was significantly lower in the cases than in the controls. In the multivariate analysis, older age, obesity at 1 year of age, and a high red meat intake were independently and significantly associated with the risk of developing mammary tumor and dysplasias.

Animals↗

PubMedDate not supplied

Lobaplatin as an adjuvant chemotherapy to surgery in canine appendicular osteosarcoma: a phase II evaluation.

Canine osteosarcoma, the most common bone tumor in dogs, is a well-established, naturally-occurring animal model for human OS. The aim of this study was to evaluate the clinical and hematological side-effects and to assess the efficacy of lobaplatin chemotherapy in dogs with appendicular osteosarcoma as an adjuvant therapy to surgical resection. Twenty-eight dogs without systemic signs of disease were treated with surgical resection of the tumor and adjuvant lobaplatin chemotherapy at a dose of 35 mg/m2, i.v., once every three weeks, for a maximum of 4 doses. Clinical signs of toxicosis were uncommon and consisted mainly of vomiting and depression. Hematological signs of toxicoses were common 7 to 10 days after lobaplatin chemotherapy and consisted of thrombocytopenia, leukopenia and neutropenia. All the signs were transient and most disappeared within three weeks of lobaplatin administration. A one-year disease-free fraction of 21.8% and a one-year survival fraction of 31.8% were calculated. Multivariate Cox regression analyses showed that a high histological tumor grade and presence of metastasis in the tumor vessels were associated with significantly shorter disease-free interval and survival time. Also, an increased pretreatment plasma alkaline phosphatase level at first presentation and a high histological level of tumor necrosis were associated with a shorter survival interval. Lobaplatin was easy to administer as an i.v. bolus injection at a three-week interval in dogs without the need for pretreatment infusions.

Animals↗

PubMedDate not supplied

Flow-cytometric DNA ploidy analysis in primary and metastatic canine thyroid carcinomas.

DNA ploidy was measured by flow cytometry in 36 primary malignant thyroid neoplasms (including 6 bilateral tumours which were considered as separate neoplasms) from 30 dogs. In addition, DNA ploidy was determined in local recurrences in 3 dogs, and in 18 metastatic sites from 14 dogs. Aneuploidy was found in 21 of 36 (58%) primary sites. Eighteen of the 21 (86%) aneuploid tumours contained hypodiploid cell populations, with 12 having single hypodiploid peaks, and 6 being multiploid. Three other tumours had single aneuploid peaks with a DNA index (DI) greater than 1.0. The DIs in local recurrences were identical to those in the original neoplasms. Ploidy status (diploid vs. aneuploid) was identical in primary and metastatic sites in 10 out of the 14 dogs. Aneuploidy was more frequent in carcinomas from dogs with distant metastases (78%) than from dogs with less advanced stages of disease (53%), although this difference was not significant. There was no significant correlation between DNA ploidy and histopathological variables. From the strikingly high frequency of hypodiploidy in canine tumours, it is concluded that ploidy evolution in canine neoplasms may differ from that in human tumours.

Aneuploidy↗

PubMedDate not supplied

Hormones and mammary tumour disease in the female dog: an update.

In both toxicity studies and epidemiologic studies in veterinary medicine it has been demonstrated that ovarian steroids as well as many synthetic derivatives may enhance mammary tumour formation in the dog. Abnormalities in pituitary function, in particular of growth hormone secretion, have been assumed to take part in this process. In this paper the pathogenetic role that endogenous and exogenous hormones may have in canine mammary tumourigenesis is reviewed. The available evidence suggests that steroid hormones act at an early stage in the development of tumours by stimulating the proliferation of normal epithelium. This leads to an increase in the number of susceptible cells. A growth-stimulatory action may further be exerted upon cells that have undergone partial malignant transformation, but possibly to a lesser extent upon fully malignant cells at a late stage of tumour development. In advanced mammary cancers steroid receptor presence is infrequent, which may indicate a more autonomous pattern of growth. No support has been found for the earlier assumption that growth hormone overproduction is an important factor in canine mammary tumourgenesis. The role of prolactin and thyroid hormones in this process remains uncertain.

Animals↗

PubMedDate not supplied

Cytogenetic analysis of cell lines derived from metastases of a mammary carcinoma in a dog.

Three cell lines derived from two metastases of a mammary carcinoma in a female dog were analyzed cytogenetically. All three cell lines showed a modal chromosome number of 76, with ranges of 74-77, 72-78, and 73-78. A biarmed chromosome in addition to the X chromosomes was observed in all cells of one cell line, and in a part of the cells of the other two cell lines. Results of banding analyses indicated that this chromosome was identical in the three cell lines, and can thus be considered a clonal marker. Additional biarmed chromosomes have not been reported previously from mammary tumor cells, although their presence is rather common in other canine neoplasms.

Animals↗

PubMedDate not supplied

Anterior pituitary function in female dogs with spontaneous mammary tumors: I. Growth hormone.

It has been hypothesized that growth hormone (GH) plays a major role in the pathogenesis of canine mammary tumor disease. In order to test this hypothesis, plasma GH levels were measured at rest and during dynamic function tests in dogs with benign or malignant proliferative mammary lesions and in control dogs. Both in control dogs and in dogs with benign disease, basal GH levels were found to be elevated during both metestrus and progestin treatment, as compared to anestrus. Dogs with benign or malignant disease did not have higher basal GH levels than control dogs matched for the effect of endogenous or exogenous progestin exposure. The GH response to glucose or thyrotropin releasing hormone (TRH) did not vary significantly with progestin exposure, nor between the 3 groups of animals. The stimulatory effect of clonidine upon GH secretion was reduced in dogs with benign or malignant disease as compared to controls matched for the effect of progestin exposure. These findings indicate that mammary tumor disease in the dog is associated with a disturbance in the regulation of GH release.

Animals↗

PubMedDate not supplied

Anterior pituitary function in female dogs with mammary tumors: II. Prolactin.

Plasma prolactin (PRL) concentrations at rest and during dynamic tests were measured in dogs with benign or malignant proliferative mammary lesions and in age-matched healthy control dogs. Basal PRL concentrations of dogs with benign or malignant lesions were not found to be elevated in comparisons controlled for the effects of estrous cycle phase or progestin treatment. A statistically non-significant increase of the PRL response to thyrotropin-releasing hormone (TRH) was seen in separate groups of affected dogs as compared to matched controls. A tendency towards a significantly elevated response to TRH appeared in the combined (benign plus malignant disease) group of affected dogs in anestrus (P = 0.05) and in metestrus (P = 0.09). The PRL response to clonidine was very variable and did not differ between the 3 groups of dogs. The bromocriptine-induced suppression of PRL secretion did not vary significantly among the three groups. These results do not indicate an unequivocal association of mammary tumor development and altered PRL secretion. It is only warranted to conclude that in some dogs the occurrence of benign or malignant mammary lesions is associated with hyper-responsiveness of the PRL secretion to stimulation with TRH.

Animals↗

PubMedDate not supplied

Feline mammary carcinomas as a model for human breast cancer. II. Comparison of in vivo and in vitro adriamycin sensitivity.

Feline mammary carcinomas were tested for their in vitro and in vivo sensitivity to Adriamycin. In vitro, twenty randomly chosen tumor islands were studied to test the effect of concentrations of the drug ranging from 0.25-2.00 micrograms/ml. In vivo, parts of primary tumors left in situ after surgical biopsy were used to assess the response to five i.v. injections of 30 mg/m2 Adriamycin. When comparing the in vitro and in vivo response, the best sensitivity (100%) was obtained using 2.00 micrograms/ml Adriamycin and the best specificity (75%) using 1.00 microgram/ml Adriamycin, both in vitro. Tumors recurring after treatment showed acquired resistance in vitro.

Adenofibroma↗

PubMedDate not supplied

Prolactin binding in benign and malignant mammary tissue of female dogs.

Prolactin receptor (PRL-R) concentrations were determined in membrane preparations of canine mammary tumours and of non-affected mammary tissues by a radioreceptor-assay using ovine prolactin (oPRL) both for 125I-labelling and for displacement. Receptor levels greater than or equal to 3 fmol/mg membrane protein were considered positive. Histologically non-affected samples of mammary tissue from 6 dogs were PRL-R positive (12-195 fmol/mg protein). These levels were positively correlated with epithelium content (based on surface area in microscopic sections; r = 0.943, P less than 0.02). In tumour samples where pre-existing mammary epithelium (PME) was present (3 non-malignant and 6 malignant tumour samples; PME content 5-10%), the cut-off limit for PRL-R positivity was increased to 50 fmol/mg protein to forestall false positives due to non-affected tissue. If no PME was present the general limit of 3 fmol/mg protein was maintained. All 18 non-malignant tumours showed PRL-R (18-162 fmol/mg protein). The PRL-R levels were positively correlated with levels of oestrogen-(ER; r = 0.735, P less than 0.002) and progesterone receptors (PgR; r = 0.556, P less than 0.02) as measured by a multi-concentration dextran-coated charcoal method. ER and PgR levels were also proportional (r = 0.660, P less than 0.01). In 6 dogs bearing primary cancers with 5-10% PME, 1 out of a total of 6 tumours was PRL-R positive. In 9 dogs bearing primary or locally recurrent cancers without PME, significant PRL-R levels were measured in 2 out of a total of 10 tumours. Three metastatic sites in 2 other dogs were PRL-R positive. In 2 dogs (1 with a PRL-R negative local recurrence) the metastatic lesions were PRL-R negative. Thus 5 dogs of a total of 18, had PRL-R positive mammary cancers (3-377 fmol/mg protein). Unlike in non-malignant lesions the ER, PgR, and PRL-R levels were not related. In mammary cancer the presence of PRL-R was less common (P less than 0.001), and the ultimate levels less high (P less than 0.001) than in non-malignant tumours. In comparative studies using pooled membrane preparations from benign mammary tissues, oPRL was far more effective than canine prolactin (cPRL) in displacing 125I-oPRL; canine growth hormone (cGH) in this respect was ineffective. It is concluded that non-malignant mammary tissue in the dog generally is PRL-R positive; only some mammary cancers retain the PRL receptors.

Animals↗

PubMedDate not supplied

The occurrence of estrogen and progestin receptors and anti-estrogen binding sites (AEBS) in canine non-Hodgkin's lymphomas.

In the present study the occurrence of estrogen and progestin receptors in the lymphoid tissue of 20 canine non-Hodgkin's Lymphoma patients was investigated. Lesions in all dogs were histologically classified according to criteria used in human patients. No progestin receptors could be demonstrated. Estrogen receptors were found only in the cytosol of two canine lymphomas. Antiestrogen binding sites were present in all 18 cases examined (range 37-356, median 110 fmol/mg protein). No correlation with age, sex or histological classification was found. A pilot study was carried out in five of these dogs that were negative for estrogen receptors and positive for antiestrogen binding sites. These dogs were treated with the antiestrogen tamoxifen (20-30 mg/day) for 2-3 weeks, but the treatment had no apparent effect. It was concluded that if antiestrogens do play a role in the treatment of non-Hodgkin's lymphoma in the dog, it is most likely not by means of antiestrogen binding sites.

Animals↗

PubMedDate not supplied

The canine p53 gene is subject to somatic mutations in thypoid carcinoma.

In many different types of tumors in man and mouse, p53 is the tumor suppressor gene most frequently affected by a combination of somatic mutation and loss of the wildtype allele. In order to develop a molecular tool to study the genetic evolution of tumors in the dog, we have cloned an evolutionary conserved part of the canine homologue of p53. The isolated genomic segment, 534 bp in length, contains the 3' half of exon 5, the complete exon 6 and the 5' half of exon 7, as well as the intronic intervening sequences. The gene organization of this segment shows strong homology to that published earlier for a number of other species, including man, mouse, and Xenopus laevis. This conservation is apparent at the DNA sequence level, as well as at the deduced aminoacid sequence level. mRNA expression can be detected at low levels in normal tissues with increased mitotic activity, and in the Madin-Darby canine kidney cell line. A-->G T transversion was found in 1 out of 23 investigated primary thyroid carcinomas at a position corresponding to codon 174 in the human p53, and was predicted to give rise to an aminoacid substitution in the protein. These results suggest that p53 plays a role in the development of malignancy in the dog, in a way comparable to that in man.

Amino Acid Sequence↗

PubMedDate not supplied

The difference in DNA ploidy pattern between some canine and human neoplasms appears to be genuine and a reflection of dissimilarities in DNA aneuploidy evolution.

In a reaction to the article by Deitch et al, (Anticancer Res 13: 2117-2118, 1993) evidence is presented that flow cytometrically detected DNA-hypodiploidy in canine neoplasms is genuine and not an artefact caused by autolysis or chemotherapy. Intervals between removal of tumors and freezing in our studies were much shorter (average 15 min, maximum 30 min) than e.g. for human breast tumors in which the percentage of hypodiploidy is about 2%. Also average CVs for the G0, 1 peaks in our FCM analysis of canine tumors (mammary 2.27 + 0.06, n = 179); thyroid 2.57 + 0.13, n = 88) were equal to or less than those usually found in the comparable human tumors. Biological arguments in favor of the existence of genuine hypodiploid stemlines are the finding of tetraploidized subclones of the original hypodiploid clone, the reappearance of the same hypodiploid stemline in distant metastases during clinical follow up, and the isolation of a cytogenetically and flow cytometrically hypodiploid cell line from a primary canine mammary carcinoma. It is concluded that Deitch et al, incorrectly have invoked autolysis as a source of hypodiploidy in our original studies on canine neoplasms. Our evidence for interspecies differences in the evolution of aneuploidy in tumors of the same organ therefore remains unchallenged.

Aneuploidy↗