Mammary Tumors In Dogs Research Articles

Evaluation of interleukins 8 and 12, CA 15-3 and free circulating DNA as prognostic markers in dogs with mammary tumors

Background Mammary tumors of dogs are an excellent model to investigate the clinical and pathological diagnosis and prognosis of cancer. Interleukins play a key role in cancer, particularly interleukin-8, which has tumorigenic and pro-angiogenic properties and interleukin-12, with anti-metastatic and angiogenic properties. The carbohydrate antigen tumor marker (CA 15-3) has important clinical significance in the monitoring of patients with breast cancer and, in addition, free circulating DNA has been considered a candidate biomarker for cancer. The aim of this study was to measure serum levels of interleukin-8, 12, CA 15-3 and to estimate the number of copies of CAN SINE sequences to correlate with clinicopathological parameters and survival.

The effect of neutering on the risk of mammary tumours in dogs – a systematic review

A commonly-stated advantage of neutering bitches is a significant reduction in the risk of mammary tumours, however the evidence for this has not previously been assessed by systematic review. The objectives of this study were to estimate the magnitude and strength of evidence for any effect of neutering, or age of neutering, on the risk of mammary tumours in bitches. A systematic review was conducted based on Cochrane guidelines. Peer-reviewed analytic journal articles in English were eligible and were assessed for risk of bias by two reviewers independently. Of 11,149 search results, 13 reports in English-language peer-reviewed journals addressed the association between neutering/age at neutering and mammary tumours. Nine were judged to have a high risk of bias. The remaining four were classified as having a moderate risk of bias. One study found an association between neutering and a reduced risk of mammary tumours. Two studies found no evidence of an association. One reported "some protective effect" of neutering on the risk of mammary tumours, but no numbers were presented. Due to the limited evidence available and the risk of bias in the published results, the evidence that neutering reduces the risk of mammary neoplasia, and the evidence that age at neutering has an effect, are judged to be weak and are not a sound basis for firm recommendations.

Prognostic studies of canine and feline mammary tumours: The need for standardized procedures

For several years, veterinary oncologists have been struggling with the prognosis of mammary tumours in dogs and cats. Translation of tumour characteristics into prognostic information is an invaluable tool for the use of the most appropriate therapies, as well as for planning innovative therapeutic trials. Moreover, canine and feline spontaneous mammary gland tumours are good models for the study of human breast cancer. Collecting and interpreting information regarding the prognosis of canine and feline mammary tumours is difficult due to the fact that different methods have been applied to study various components and characteristics. This review identifies some of the challenges of prognostic studies of spontaneous canine and feline mammary tumours and suggests standardized procedures to overcome these challenges and facilitate reproducibility and assessment of results.

Cytologic examination of fine‐needle aspirates from mammary gland tumors in the dog: diagnostic accuracy with comparison to histopathology and association with postoperative outcome

Mammary tumors are the most common neoplasms in female dogs. Malignant tumors may carry a poor prognosis and necessitate surgery. Few data are available on the value of cytologic examination as a diagnostic or prognostic tool for mammary tumors in dogs. The objectives of this study were to determine whether cytologic findings in fine-needle aspirate specimens of canine mammary tumors correlate with histopathologic results and whether the cytologic diagnosis is associated with postoperative outcome. In this prospective study, fine-needle aspirate samples were obtained from 50 mammary tumors in 50 dogs. Results of cytologic and histopathologic examination were compared, using the histologic diagnosis as the reference method. Kaplan-Meier log rank analysis was used to evaluate univariate association of the cytologic diagnosis with duration of survival, local control, and metastasis-free interval. Adequate cytologic samples were obtained in 43/50 (86%) cases. The cytologic diagnosis correlated with the histologic diagnosis for benign and malignant tumors in 40/43 (93%) and 35/43 (81%) cases, respectively. Cytologic examination had a sensitivity of 88% and a specificity of 96% for the diagnosis of malignancy. The cytologic diagnosis had significant univariate association with duration of survival (P=.016), recurrence-free interval (P=.003), and metastasis-free interval (P=.014). Cytologic examination of mammary tumors in the dog has satisfactory accuracy, sensitivity, and specificity for the diagnosis of malignancy and is associated with postoperative outcome. Further studies on the diagnostic accuracy of cytology as well as multivariate analysis of its preoperative prognostic value in mammary tumors in the dog are warranted.

Evaluation of serum haptoglobin and C‐reactive protein in dogs with mammary tumors

In veterinary medicine, there is increasing interest in measuring acute phase proteins as a tool in the diagnosis and monitoring of neoplastic diseases. Although mammary neoplasms are the most common type of cancer in dogs, acute phase proteins have not been extensively evaluated in dogs with mammary tumors. The aim of this study was to evaluate serum haptoglobin (Hp) and C-reactive protein (CRP) concentrations in the dogs with mammary tumors and assess their potential association with malignancy. A retrospective study of dogs with mammary tumors was performed. Serum concentrations of CRP and Hp were determined in healthy control dogs (n=20) and dogs with mammary tumors before surgery (n=41). Mammary tumors were grouped as carcinomas (n=24), fibrosarcoma (n=1), malignant mixed tumors (n=7), benign mixed tumors (n=6), and adenomas (n=3). CRP and Hp concentrations were compared in dogs with different tumor types and were also compared based on tumor size, lymph node infiltration, skin ulceration, fixation to underlying tissue, and time between tumor identification and removal. Hp concentration was significantly (P<.043) higher in dogs with mammary tumors (median 2.03 g/L, range 0.09-2.94 g/L) compared with controls (1.38 g/L, range 0.08-3.00 g/L), but the range of values overlapped considerably. CRP concentration was higher in dogs with carcinomas (4.70 mg/L, range 0.63-128.96 mg/L) vs controls (2.11 mg/L, range 0.25-6.57 mg/L) (P=.0008) and in dogs with ulcerated skin (14.8 mg/L, range 5.7-128.9 mg/L, n=3) compared with those without ulceration (2.4 mg/L, range 0.11-30.3 mg/L, n=38) (P=.048). Serum Hp and CRP do not appear to have value in diagnosing or predicting malignancy of mammary tumors in dogs. Higher CRP concentrations in dogs with mammary carcinoma suggest a role for inflammation in this tumor type.

Novel variations and loss of heterozygosity of BRCA2 identified in a dog with mammary tumors

To establish novel polymorphic markers for analysis of loss of heterozygosity (LOH), so as to study the possible involvement of BRCA2 in mammary tumors obtained from dogs. Blood samples, mammary gland specimens, or mammary tumors from 3 tumor-bearing dogs and 10 tumor-free dogs. Nucleotide sequence analysis was performed with a DNA autosequencer. Loss of heterozygosity analysis was performed for markers established in the present study. The expression level of canine BRCA2 was quantified by real-time PCR analysis. 3 novel microsatellite markers with high heterozygosity rates (> 50%) were established, and the previously reported marker for canine BRCA2 gene locus was improved. These markers were used for the analysis of DNA from formalin-fixed and paraffin-embedded samples. By use of these markers, LOH in canine BRCA2 was identified as a result of recombination. In mammary tumor DNA that corresponded to the LOH-positive dog, the level of canine BRCA2 expression was decreased compared with that of nonneoplastic mammary gland tissue; the open reading frame contained 4 missense variations, 1 insertion variation, and 1 silent variation, some of which were localized to functional domains. 3 novel polymorphic markers were developed for LOH analysis of canine BRCA2 and identified a dog with LOH with some variations in the functional domains. These markers could be useful for assessing the relevance of BRCA2 variation in mammary tumors of dogs.

Mammary tumours in dogs and cats

COMPANION animal mammary gland neoplasias are common conditions seen in general practice. Most can be managed by surgical resection and there is usually no need for referral. The majority of...

Adjuvant gemcitabine after surgical removal of aggressive malignant mammary tumours in dogs

Canine mammary tumours are generally treated with surgery alone, despite the fact that 50% of them are malignant and many will eventually lead to recurrence or metastases. A prospective clinical trial in which dogs with aggressive mammary carcinoma of clinical stages IV and V were treated with surgical excision (n = 9) or with surgery and adjuvant weekly gemcitabine (n = 10) for at least four cycles was conducted. Gemcitabine was given as an intravenous infusion at the dose of 800 mg m(-2). Aim of the study was to explore potential beneficial effects of gemcitabine on time to local recurrence (TTR), time to distant metastases (TTM) and overall survival (OS) in canine patients with operated mammary tumours bearing high risk for locoregional failure and distant metastases. Also, factors associated with OS, including neutering status, body weight, age, clinical stage at presentation, tumour size, histological grade and, in dogs receiving chemotherapy, the number of gemcitabine treatments, were investigated. Finally, acute toxicities related to chemotherapy and quality of life were assessed in dogs receiving gemcitabine. Dogs treated with surgery alone or surgery followed by gemcitabine had no difference in TTR, TTM or OS (P > 0.05). In the group of dogs receiving adjuvant chemotherapy, the number of gemcitabine treatments was positively correlated with OS (P = 0.017). Gemcitabine treatment was well tolerated, with no dogs experiencing clinically relevant haematological or gastrointestinal toxicity. Despite being safe at the present dose, gemcitabine chemotherapy as an adjunct treatment to surgical excision may not be recommended in dogs with aggressive mammary carcinoma.

Comparison of B-mode and Doppler ultrasonographic findings with histologic features of benign and malignant mammary tumors in dogs

To compare and correlate B-mode and color Doppler ultrasonographic characteristics with the histologic findings of benign and malignant mammary tumors in dogs. 49 mammary tumors in 26 dogs. Before excision, tumors were evaluated via B-mode and color Doppler ultrasonography to assess size, echogenicity, echopattern, acoustic transmission, invasiveness, and vascularity. Paraffin-embedded microsections of the tumors were stained with H&E and examined for presence of necrosis, cysts, cartilage, bone, mineralization, invasion of surrounding tissue, and tissue heterogeneity. To assess vascularity, the number and distribution of vessels that were stained by the Verhoeff van Gieson technique were recorded. Tumor echogenicity and echopattern on ultrasonographic images correlated with tissue heterogeneity detected histologically. Acoustic enhancement was correlated with the presence of necrotic or cystic areas. Tumor invasion into surrounding tissues as determined ultrasonographically did not correlate with the histologic findings. There was a significant correlation between the number of detected vessels and distribution of flow within the tumors determined via ultrasonographic and histologic examinations. In canine mammary tumors, ultrasonographic characteristics appear to be correlated with histopathologic changes. Data suggest that ultrasonography may have an important role in the evaluation of mammary tumors in dogs, particularly in the evaluation of tissue composition and tumor vascularity.

Detection of lymph node micrometastases in malignant mammary tumours in dogs by cytokeratin immunostaining

A series of 131 local and regional lymph nodes from 40 dogs with malignant mammary tumours were evaluated by staining with haematoxylin and eosin and immunohistochemically for antibodies to pancytokeratin...

The Activity of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) in Mammary Tumors of Dogs and Rats

We conducted zymography for detecting the activity of matrix metalloproteinases (MMPs) and reverse zymography for the activity of tissue inhibitors of metalloproteinases (TIMPs) in canine spontaneous and rat 7, 12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor tissues. The activities of MMPs of canine mammary tumors were quite higher than those of the rat chemically induced tumors. The activities of MMPs were significantly higher in malignant tissues than in benign ones of canine tumors, whereas the activity of only MMP-2 was higher in both benign and malignant rat tumors compared to normal tissues. There were no differences of MMPs activities between benign and malignant rat tumors. The results of reverse zymography indicated that the activities of TIMP-1, -2 and -3 were strikingly higher in rat tumors than in canine tumors. The activities were higher in malignant tissues than in benign ones of dogs, and higher in tumor tissues than in normal mammary tissues of rats. The results of film in situ zymography for tissue localization of gelatinolytic activity showed that the digested area was more extended in malignant tumors than in benign ones of dogs. However, the area was similarly extended in both benign and malignant rat tumors. These results may indicate that the canine spontaneous malignant mammary tumors possess more aggressive nature than the rat chemically induced counterpart, resulting from the high level of MMPs and low level of TIMPs activities of the tumor tissues.

Cyclooxygenase ‐2 Expression in Mammary Tumors in Dogs and its Correlation to Histologic and Biologic Behavior

Introduction: Cyclooxygenase‐2 (Cox‐2) is the inducible form and the rate‐limiting enzyme, for conversion of arachidonic acid to prostaglandins. Cox‐2 overexpression, common in carcinomas, is associated with increased growth rate, resistance to apoptosis, angiogenesis, and overall, both local and distant aggressive behavior. Cox‐2 overexpression has been detected in human and canine mammary tumors (MTs). Histopathology of canine MT is not always predictive of biologic behavior, and anecdotally, only 50% of the malignant MTs are expected to metastasize. We hypothesize that Cox‐2 expression correlates with aggressive behavior.Methods: This retrospective study evaluated 48 bitches, presented for excision of MT between 2000 and 2003 at FMVZ de Botucatu‐UNESP, Brasil. Follow‐up varied from 18 months to 24 months and included physical examination and thoracic radiographs. Histopathologic examination was performed in all tumors, as well as in metastatic lesions when detected in the follow‐up period. Immunohistochemistry was used to detect expression of Cox‐2 in paraffin blocks (Rabbit polyclonal anti‐PGHS‐2. Oxford Biomedical). 10 adenomas, 10 carcinomas, 10 benign mixed tumors, 10 malignant mixed tumors and 8 cases of primary carcinomas and their metastatic lesions.Results: Expression of Cox‐2 varied among groups. Adenomas (32.1%), mixed benign tumors (38%), carcinomas (60.3%), malignant mixed tumors (65.8%), and metastatic carcinomas (81.25%) and their metastatic lesions (84.35%). Statistically significant differences (p &lt; 0.05) were observed between the benign and malignant counterparts and between carcinomas and metastatic carcinomas.Conclusions: Cox‐2 expression correlates with both histologic and biologic behavior in mammary carcinomas, and may serve as a predictor of metastatic potential.

Retrospective review and systematic study of mammary tumors in dogs and characteristics of the extracellular matrix

A finalidade do presente trabalho foi efetuar um estudo retrospectivo, de 1932 a 1999 , afim de se estabelecer a casuistica desses tumores nos arquivos do Departamento de Patologia da Faculdade de Medicina Veterinaria - USP , bem como a frequencia de desmoplasia, metaplasia cartilaginosa e ossea em 578 desses tumores. Entre os 537 tumores malignos, 13.05% foram adenocarcinomas tubulares simples, 3.91% foram adenocarcinomas tubulares compostos, 7.26% adenocarcinomas papiliferos simples, 4.28% adenocarcinomas papiliferos compostos, 23.27% cistoadenocarcinomas papiliferos simples, 8.37% cistoadenocarcinomas papiliferos compostos, 16.38% adenocarcinomas solidos simples, 6.70% adenocarcinomas solidos compostos, 2.04% carcinomas de celulas espinhosas simples, 1.11% carcinomas de celulas espinhosas compostos, 2.79% carcinomas mucinosos ,8.19% carcinomas anaplasicos ,0.93% carcinomas escamosos, 1.30% fibrossarcomas,.0.18% condrossarcoma, 0.18% osteossarcoma e entre os 41 tumores benignos ,51.21% foram adenomas, 12.19% cistadenomas pailiferos,7.31% papilomas, 4.87% fibroadenomas e 24.39% foram fibroadenomas. Tanto a desmoplasia como a metaplasia foi um achado frequente nas neoplasias benignas e malignas, mas foram mais frequentes entre os adenocarcinomas tubulares compostos: 38% apresentaram desmoplasia, 57% metaplasia cartilaginosa e 28% metaplasia ossea. Entre as neoplasias benignas, adenoma apresentou a maior frequencia: 14 % com desmoplasia, 29% com metaplasia cartilaginosa e 24% com metaplasia ossea. Os resultados deste estudo enfatizam a complexidade da inter-relacao entre as macromoleculas da matriz extracelular e as celulas tumorais.

The Prognostic Significance of Angiogenesis in Canine Mammary Tumors

The purpose of the study was to determine if neovascularization, a measure of angiogenesis, is correlated with metastasis of mammary tumors in dogs. Forty‐six paraffin‐embedded tissue blocks of benign and malignant canine mammary tumors obtained from 42 clinical cases at the Iowa State University Veterinary Teaching Hospital were retrieved from the archives of the Department of Veterinary Pathology. Of the dogs with malignant tumors, cases with and without lymph node metastasis were chosen. Neovascularization was quantified by light microscopy on formalin‐fixed, paraffin‐embedded sections of canine mammary tumors using an avidin‐biotin immunoperoxidase assay for factor VIII‐related antigen. Mean microvessel counts for each group were statistically evaluated using analysis of variance. The mean number of microvessels was highest in the malignant tumors of dogs with lymph node metastasis (44). This number was significantly different from the mean number of microvessels in the benign tumors (28; P= .03) and a trend occurred toward higher microvessel counts in malignant tumors with lymph node metastasis versus malignant tumors of dogs without metastasis (32; P= .1). No significant difference was found between the number of microvessels found in malignant tumors without metastasis versus benign tumors. The trend toward higher microvessel counts in mammary tumors that have metastasized supports the premise that angiogenesis may be an independent and significant prognostic indicator in dogs with malignant mammary tumors, as it is in women with breast cancer.

The prognostic significance of angiogenesis in canine mammary tumors.

The purpose of the study was to determine if neovascularization, a measure of angiogenesis, is correlated with metastasis of mammary tumors in dogs. Forty-six paraffin-embedded tissue blocks of benign and malignant canine mammary tumors obtained from 42 clinical cases at the Iowa State University Veterinary Teaching Hospital were retrieved from the archives of the Department of Veterinary Pathology. Of the dogs with malignant tumors, cases with and without lymph node metastasis were chosen. Neovascularization was quantified by light microscopy on formalin-fixed, paraffin-embedded sections of canine mammary tumors using an avidin biotin immunoperoxidase assay for factor VIII-related antigen. Mean microvessel counts for each group were statistically evaluated using analysis of variance. The mean number of microvessels was highest in the malignant tumors of dogs with lymph node metastasis (44). This number was significantly different from the mean number of microvessels in the benign tumors (28; P = .03) and a trend occurred toward higher microvessel counts in malignant tumors with lymph node metastasis versus malignant tumors of dogs without metastasis (32; P = .1). No significant difference was found between the number of microvessels found in malignant tumors without metastasis versus benign tumors. The trend toward higher microvessel counts in mammary tumors that have metastasized supports the premise that angiogenesis may be an independent and significant prognostic indicator in dogs with malignant mammary tumors, as it is in women with breast cancer.

Computer-assisted image analysis of intratumoral vessel density in mammary tumors from dogs

Abstract Objective To determine whether intratumoral microvessel density can be used to distinguish benign from malignant mammary tumors in dogs and to predict the outcome of surgical treatment for small volume (&lt; 3-cm diameter) tumors. Sample Population Tissue sections from 58 mammary tumors (42 malignant and 16 benign) from dogs. Procedure Mammary tumors were stained by immunohistochemistry for factor VIII-related antigen. Computer-assisted image analysis was used to determine intratumoral vessel density in immunostained areas. Total vascular density (TVD), calculated from 3 non-overlapping fields, was analyzed for correlation with patient or tumor histomorphologic characteristics, and results obtained by surgical treatment of small volume tumors. Results Mean TVD of malignant tumors was significantly greater than that of benign tumors. Total vascular density was not correlated with patient age, sex, reproductive status, clinical tumor stage, or histologic type. For small volume (&lt; 3-cm diameter) malignant tumors, mean TVD was higher in tumors that recurred after surgery than in tumors that did not recur; however, TVD was not predictive of time to recurrence. Conclusion and Clinical Implications Immunohistochemistry and computer-assisted image analysis allowed objective quantitation of intratumoral microvessel density in formalin-fixed, paraffin-embedded tissue sections. Tumors with high TVD were more likely to recur after surgical treatment than tumors with low TVD suggesting that TVD measurements can be used by the clinician, in addition to histologic type and clinical stage, to predict prognosis after surgical treatment. These data also provide rationale for use of antiangiogenesis strategies for treatment of malignant mammary tumors in dogs. (Am J Vet Res 1998;59:1238-1242)

More about Mammary Tumors in Beagles Given Radium-226

A recently published paper from this laboratory (1) reported an excess of malignant mammary tumors among female beagles injected with 226Ra as compared with female control beagles (among 226Ra dogs, there were 34 expected and 66 observed, P < 0.005). A corresponding excess was not seen for benign mammary tumors. There seemed to be no difference between dogs given 226Ra and controls in the appearance time for the first malignant mammary tumor, but there was an indication that the timing of subsequent mammary cancers (three or more per animal) was affected by 226Ra exposure. Neither ovariectomy nor exposure to diagnostic X rays could be shown to be associated with the difference between controls and dogs given 226Ra with regard to mammary malignancies. It was proposed in that report (1) that the increased risk of mammary cancer might have been a result of (a) initial deposition of 226Ra in sensitive tissue, or (b) transient deposition of 226Ra progeny in the mammae, or (c) a general effect on the immune system of skeletal a-particle irradiation by radium and its progeny that might reduce the resistance to expression of mammary neoplasia. Since our report was accepted for publication, we have had the opportunity to examine the mammary tumor experience among comparable female beagles given injections of either 241Am or 239pu. Both of these radionuclides are a-particle emitters and also irradiate the skeleton. However, no such differences in mammary tumor frequency between dogs given 241Am or 239pu and controls could be detected. These data have some relevance to the third of the three possibilities given above that were discussed by Bruenger et al. (1). Reports dealing with the analysis of soft-tissue tumors in our beagles given 241Am or 239Pu have been submitted for publication or are in preparation. Not included in the published version of our paper on mammary tumors in dogs given 226Ra was an analysis of the comparison between irradiated beagles and controls with respect to the number of separate dates on which mammary tumors were diagnosed in the individual animals. An excess of malignant tumors in the dogs given 226Ra could have been a result of (a) a greater average number of dates on which tumors were diagnosed, (b) a larger average number of tumors diagnosed at each diagnosis date or (c) a combination of both (a) and (b). Table I exhibits the results of this comparison. It appears from the data in Table I that there cannot be established a difference in the average number of dates on which tumors were diagnosed between controls and irradiated animals: Therefore, it seems more probable that the observed difference in the number of malignant tumors reported by Bruenger et al. (1) may have been a result of a larger average number of tumors diagnosed in 226Ra dogs on any one day. For many years, it has been the policy of our group to use the word dose to denote the energy imparted to matter and to designate a corresponding value that has the units of gray or rad, exclusively. To avoid confusion, we have tried (not always successfully) to use the word dosage to denote such other concepts as the amount of radioactivity adminis-

Immunological aspects of mammary tumors in dogs and cats: a survey including own studies and pertinent literature

Naturally occurring cancer in companion animals parallels cancer in man more closely than does experimentally induced cancer in inbred laboratory animals. In dogs and cats, as in man, a role for immune responses is indicated in the development of tumors. A survey is presented based on the literature and our own studies concerning the immunological and immunotherapeutic aspects of canine and feline mammary neoplasia. In dogs bearing mammary neoplasms, circulating immune complexes appear to play a negative role in the generation of effective antitumor immune responses. The functional role of peripheral blood lymphocytes and tumor-infiltrating lymphocytes in dogs and cats with mammary tumors is not yet fully established. No tumor antigen responsible for humoral or cellular responses has yet been identified. Extracorporeal perfusion of serum of dogs with mammary tumors and subcutaneous administration of mitomycin- and neuraminidase-treated autologous tumor cells are associated with improved prognosis. The opposite was true for i.v. treatment with BCG or Corynebacterium parvum vaccine in our study, in contrast to a previous report. A number of other treatment modalities in cats and dogs with mammary carcinomas failed to induce tumor regression. Canine and feline mammary carcinomas are good candidates for modern immunotherapeutic approaches.

Guidelines and requirements for the evaluation of contraceptive steroids.

Since their introduction in the early 1960s, the oral contraceptive (OCs) steroids have been subjected to preclinical and clinical investigations unprecedented in medical history. As a result of such extensive studies, it is now possible to make a comprehensive review of preclinical and clinical data on oral contraceptives. The OCs were introduced at a time when the Food and Drug Administration (FDA) was undergoing drastic changes as a result of the thalidomide tragedy, the introduction of the Kefauver-Harris Amendment, and the desire for greater control over the pharmaceutical industry. The initial requirements for the safety evaluation of OCs were identical to those of other drugs. There were no explicit requirements for OCs although it was generally felt that the requirements should be more stringent because the OCs were being used in otherwise healthy women for long periods of time and with minimal medical supervision. In the 1960s when it became apparent from ongoing studies that there was an increased incidence of mammary tumors in dogs treated with some progestins, the FDA made the decision to terminate clinical studies and established the requirement for 7- and 10-yr studies in dogs and monkeys, respectively. The primary purpose of this paper is to present an historical perspective of the evolution of the preclinical requirements for the evaluation of the safety of OCs prior to their use in the various phases (I, II, III) of clinical trials. Some proposed changes in the requirements are discussed. This information will form the basis for other presentations dealing with the safety assessment of OCs in rats, dogs, and monkeys.

Pain relief in childbirth and its consequences for the infant

species. may stimulate development of mammary carcinoma in male and/or female animals. In treated rats. this is usually accompanied by higher (males) or lower (females) incidences of benign mammary tumors, as compared with the corresponding controls. The speciesspecific neuroendocrine system. i.e.. estrogen-dependent stimulation of PRL seLretion appears to be of great importance in the pathogenesis of mammary tumors in mice and rats. On the other hand, stimulation of mammary tumors in dogs by certain progestogens or progestogen-estrogen combinations seem to be related to high mammary proliferative activity of these compounds in the dog and their stimulatory effect on highly mammotrophic canine GH. In total contrast to the sittiation in mice and rats. !ong-term treatment of the dog with high doses of estrogens does not stimulate mammary tumor development in spite of their ability to stimulate PRL secretion in this species. Similarly, in the monkey and man certain sex steroids (high doses) may stimulate PRL secretion. However, in the monkey. steroid-related mammary tumors are not observed. even after long-term treatmr’nt wath high doses of estrogens. progestogt ns and their combinations. Moreover, cc Intraceptive use appears to decrease the rjsk OI benign breast tumors in women. and after two decades of extensive use of contraceptive steroids, the evidence weighs against an association of these preparations with human breast cancer. These findings indicate that, with regard to the develop rr,ent of mammary tumors as an undesirable effect of contraceptive steroids. not otlly the species-specific neuroendocrine s! stem (e.g. stimulation of PRL and/or GH secretion) but also the susceptibility of certain species, strains or individuals seems to play a great role. This clearly illustrates the hmitations inherent in the extrapolation to man of data on steroid-related mamman tumors in various experimental animals.