Efficacy, maximal tolerated dose, and toxicokinetics of TTC-352 in rats and dogs, a partial ER agonist for metastatic ER+ breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14090-e14090
Author(s):  
Debra A. Tonetti ◽  
Rui Xiong ◽  
Jiong Zhao ◽  
Lauren Gutgesell ◽  
Arkadiusz Z. Dudek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cultures ◽  
Tumor Regression ◽  
Partial Agonist ◽  
Maximum Tolerated Dose ◽  
Female Rats ◽  
High Dose ◽  
Sprague Dawley ◽  
Preclinical Models ◽  
Range Finding

e14090 Background: The high prevalence of treatment resistance for estrogen receptor positive (ER+) breast cancer cause more deaths than all other breast cancers, despite the availability of endocrine therapeutics including selective ER downregulators (SERDs). Before tamoxifen, high dose estradiol (E2) delivered clinical efficacy slightly superior to tamoxifen. While recent clinical trials have shown efficacy of low dose E2, unacceptable side effects including vaginal bleeding, endometrial hypertrophy, and the negative perceptions of both patients and physicians limit acceptance. In preclinical models, tamoxifen resistant (TR) breast cancer is sensitive to treatment by E2. TTC-352 is an orally bioavailable selective human ERα partial agonist (ShERPA) designed to mimic E2 in causing tumor regression of TR breast cancer xenografts without uterine proliferation caused by E2 and tamoxifen. Methods: The published preclinical efficacy studies were extended to multiple TR ER+ cell lines in 3D spheroid cell cultures comparing to E2 and the SERD GDC0810. The maximum tolerated dose (MTD) was determined in Sprague-Dawley rats at: 200, 300, 600, 1000 and 2000 mg/kg by oral gavage (N = 3). Animals were observed for 7 days prior to necropsy. A single MTD range finding study was performed in dogs at: 50, 100, and 200 mg/kg TTC-352, administered orally in gelatin capsules. Based on these results, a 7-day repeated dose studies were completed at 30, 100, 300 and 1000 mg/kg/day in rats (3/sex/dose) and 15, 75, and 150 mg/kg (2/sex/dose) in dogs. Results: Growth of three TR ER+ breast cancer cell cultures in 3D was inhibited by TTC-352, which mimicked E2 and was equivalent to GDC0810. In female rats MTD was 1000 mg/kg and TTC-352 was well tolerated following a single oral dose of 200, 300, 600 mg/kg. The oral administration of TTC-352 at doses of 30, 100, and 300 mg/kg/day in rats (both sexes) and 15, 75 or 150 mg/kg/day in dogs (both sexes) for seven days was generally well tolerated. Conclusions: TTC-352 has demonstrated efficacy in preclinical models of TR breast cancer. Completed rat and dog studies indicated favorable tolerability and rapid absorption up to 300 mg/kg/day in rats and 150 mg/kg/day in dogs.

scholarly journals Efficacy of Vitex agnus in lowering prolactin level in mammary tumor induced SD rats

Biomedicine ◽  
2020 ◽  
Vol 39 (2) ◽  
pp. 380-386
Author(s):  
Maninder Kour ◽  
Kumar Megur Ramakrishna Bhat ◽  
Vinodini Nithyanandamadom Anatharaya ◽  
Shrijeet Chakraborty ◽  
Reshma Kumara Chandra
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Mammary Tumor ◽  
Tumor Regression ◽  
Tumor Development ◽  
Female Rats ◽  
Benign Tumors ◽  
Sprague Dawley ◽  
Sd Rats ◽  
Foamy Macrophages

Introduction and Aim: Breast cancer accounts for about 30% of all cancers in women. The present study aims to see the role of prolactin and Vitex agnus fruit extract in breast cancer progression in mammary tumor induced Sprague Dawley (SD) rats. Materials and Methods: Thirty-day old inbred SD female rats of body weight 70-80 grams were taken for this study. The rats were induced with N- Methyl-Nitroso-Urea for mammary tumor development. After the development of palpable and visible tumor the rats were treated with anti-prolactin drug (Cabergoline) and a prolactin lowering herb Vitex agnus Castus (VAC) for two months. After the treatment the rats were sacrificed for antioxidants estimation and histopathological section examination. Results: The rats treated with anti-prolactin drug showed benign tumors with hyperplasia and lactational change proving the presence of prolactin in the tumor tissue, whereas the plant extract showed mammary tumor regression by the presence of foamy macrophages in the histopathological sections. Results also showed treatment with cabergoline increased the GSH level and decreased the MDA level compared to tumor induced group. Conclusion: Prolactin may have a potential role in progression of breast cancer and Vitex agnus extract showed a prolactin lowering effect and facilitated in regression of the tumor.  

Impaired follicular development and endocrine disorders in female rats by prepubertal exposure to toxic doses of cadmium

2020 ◽  
Vol 36 (2) ◽  
pp. 63-75
Author(s):  
Saman Saedi ◽  
Mohammad Reza Jafarzadeh Shirazi ◽  
Mohammad Javad Zamiri ◽  
Mehdi Totonchi ◽  
Mohammad Dadpasand ◽  
...  
Keyword(s):  
Steroid Hormones ◽  
Endocrine System ◽  
Follicular Development ◽  
Female Rats ◽  
High Dose ◽  
Endocrine Disorders ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Puberty Onset ◽  
Different Doses

Cadmium (Cd) has been associated with several physiological problems including reproductive and endocrine system dysfunction resulting in temporary infertility. The principal objective of this project was to investigate the effects of prepubertal exposure to toxic doses of Cd on puberty onset, the endocrine system, and follicular development. For this purpose, 16 female Sprague-Dawley rats weaned on postnatal day (PND) 21 were randomly divided into 4 groups ( n = 4 per group). The treatments were as follows: 0, 25, 50, and 75 mg/kg/day of cadmium chloride (CdCl2) by oral gavage from PND 21 to observation of first vaginal opening (VO). The results demonstrated that prepubertal exposure to different doses of CdCl2 delays the age of VO, first diestrus, and first proestrus via altering the concentrations of estradiol and progesterone. The low level of these steroid hormones contributed to lower differentiation and maturation of follicles and it finally led to reduced ovarian reservoir of follicles and impaired follicular development. The number of atretic follicles and secondary follicles with premature cavity increased in rats that received a high dose of CdCl2, whereas the number of secondary follicles and corpora luteum decreased in the same circumstances. Taken together, these data suggest that prepubertal exposure to toxic doses of Cd delays the onset of puberty via disorderliness in the concentration of steroid hormones and reduces the ovarian reservoir of follicles, as well as folliculogenesis.

scholarly journals Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies

2017 ◽  
Vol 36 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Madhav G. Paranjpe ◽  
Jessica Belich ◽  
Tom J. Vidmar ◽  
Reem H. Elbekai ◽  
Marie McKeon ◽  
...  
Keyword(s):  
Selection Process ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Dose Selection ◽  
Range Finding ◽  
Body Weights ◽  
Vehicle Test ◽  
High Doses ◽  
Dose Levels

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

Studies of the Toxicological Potential of Capsinoids: VIII. A 13-Week Toxicity Study of Commercial-Grade Dihydrocapsiate in Rats

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 101-118 ◽  
Author(s):  
Eri Watanabe ◽  
Terutaka Kodama ◽  
Takeshi Masuyama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  
Keyword(s):  
Food Consumption ◽  
Water Intake ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Toxicity Study ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Sprague Dawley ◽  
Organ Weights

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100,300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤300 mg/kg or in females at any of the doses tested (≤1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study.

Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1044-1044 ◽  
Author(s):  
Geoffrey John Lindeman ◽  
Sheau Wen Lok ◽  
Alice Ruth Bergin ◽  
James Richard Whittle ◽  
Kylie Shackleton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Partial Response ◽  
Stable Disease ◽  
Tumor Regression ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Common Adverse Event ◽  
Royal Melbourne Hospital ◽  
Safety And Efficacy

1044 Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER+ breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER+BCL2+ metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER+ ( > 1%), BCL2+ ( > 10%, mod-high) and HER2 non-amplified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78; previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached; 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2; 13% Grade 3; No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing > 64 weeks). The median duration of response has not yet been reached (range, 12 to > 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER+BCL2+ metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.

Reproductive Toxicity Screen of Ammonium Dinitramide Administered in the Drinking Water of Sprague-Dawley Rats

1995 ◽  
Vol 11 (4) ◽  
pp. 437-448 ◽  
Author(s):  
Edwin R. Kinkead ◽  
Robin E. Wolfe ◽  
Carlyle D. Flemming ◽  
Harold F. Leahy ◽  
Daniel J. Caldwell ◽  
...  
Keyword(s):  
Drinking Water ◽  
Histopathological Examination ◽  
Reproductive Toxicity ◽  
Female Rats ◽  
Litter Production ◽  
High Dose ◽  
Ammonium Dinitramide ◽  
Sprague Dawley ◽  
Male And Female Rats ◽  
Pregnancy And Lactation

The Department of Defense is currently considering replacing ammonium perchlorate with ammonium dinitramide (ADN), a class 1.1 explosive oxidizer to be used in solid rocket propellant mixtures and explosives. This study was intended to evaluate the potential of ADN to produce alterations in paternal fertility, maternal pregnancy and lactation, and growth and development of offspring. Male and female rats received drinking water containing 0.0, 0.2, 1.0, or 2.0 g ADN/liter throughout the study. Mating occurred following 14 days of treatment. All dams, one-half the males, and representative pups were maintained for a total of 90 days of treatment. No mortality occurred in parental animals during the study. Treatment with ADN resulted in no adverse effects on mating; 92-100% of the animals mated. No treatment-related effects were seen in parental animals clinically or histopathologically. Adverse treatment-related effects were noted in maternal and paternal fertility indices, gestational indices, and live birth indices in both the mid- and high-dose groups. Litter sizes in themid- and high-dose groups were significantly smaller than those of the low-dose and control groups. Mean pup weights showed no statistically significant differences between ADN-treated pups and controls. Gross and histopathological examination of the animals failed to identify the cause for the decrease in litter production in the mid- and high-dose dams. This study indicates that ADN is a reproductive toxicant. The no-observable-effect level (NOEL) is 29 mg/kg/day, the median dose of the low-level female rats.

High-dose combination alkylating agent chemotherapy with autologous bone marrow support for metastatic breast cancer.

1986 ◽  
Vol 4 (11) ◽  
pp. 1592-1597 ◽  
Author(s):  
J P Eder ◽  
K Antman ◽  
W Peters ◽  
W D Henner ◽  
A Elias ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Metastatic Breast Cancer ◽  
Alkylating Agent ◽  
Tumor Regression ◽  
Metastatic Breast ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Prior Chemotherapy ◽  
Dose Combination

Seventeen patients with metastatic breast cancer were treated with a high-dose combination chemotherapy regimen and autologous bone marrow support. Thirteen patients had prior combination chemotherapy. Fifteen patients were treated with a phase II regimen of cyclophosphamide (5.625 g/m2), cisplatin (165 mg/m2), and BCNU (600 mg/m2). Bone marrow harvest and reconstitution were uncomplicated. All patients became profoundly myelosuppressed. Fourteen of 16 evaluable patients (88%) responded, including six complete responses (CRs) (38%). The median time to tumor progression was 5 months. The median survival was 8 months. CRs occurred more frequently in patients with no prior chemotherapy for metastatic disease, inflammatory breast cancer; and patients treated within 3 months of first recurrence. The rate of tumor regression was rapid, with a median of 11 days to partial response (PR) and 12 days to CR. Those patients achieving a PR by day 7 had a greater likelihood (P = .03) of attaining a CR than those patients whose PR occurred later. Three deaths (18%) occurred, all in women with inflammatory breast cancer treated with prior chemotherapy. High-dose combined alkylating agent therapy produced high PR and CR rates in metastatic breast cancer patients, most of whom had failed prior chemotherapy. The rate of tumor regression was rapid. Current efforts are directed at developing a regimen using drugs specifically active in breast cancer, with an intent of combining an effective high-dose regimen with additional modalities of therapy in the treatment of breast cancer.

USING COMPUTER SIMULATIONS FOR EVALUATING THE EFFICACY OF BREAST CANCER CHEMOTHERAPY PROTOCOLS

1999 ◽  
Vol 09 (04) ◽  
pp. 599-615 ◽  
Author(s):  
ELIEZER SHOCHAT ◽  
DVORA HART ◽  
ZVIA AGUR
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Tumor Regression ◽  
Metastatic Breast ◽  
Power Laws ◽  
Model Parameters ◽  
High Dose ◽  
Cancer Disease ◽  
Treatment Protocols ◽  
Toxic Dose

The fundamental strategy of chemotherapy is to maximize tumor eradication within the limits of tolerable toxicity to the organism. To demonstrate the use of mathematical models in designing treatment protocols, we modeled the effect of chemotherapy on tumor mass and simulated the outcome of several neoadjuvant protocols for breast cancer disease. The model assumes unperturbed tumor growth, superimposed by periods of tumor regression during treatment applications. It takes into account both cell cycle specific (CCS) and cell-cycle non specific drugs (CCNS). Three possible modes of growth (exponential, Gompertz and power laws) were simulated in the study. The model parameters (such as cytotoxic activity of a given protocol) were estimated by best fit procedure from the clinical data of tumor regression following neoadjuvant treatments. The estimated parameters were then used to simulate various regimens that are employed today in the treatment of adjuvant and metastatic breast cancer. Our results suggest that although high dose chemotherapy (HDT) cannot eradicate overt metastatic disease, it may lead to cure if applied early in the natural history of breast cancer. Moreover, the simulations predict a better response for a rather toxic dose dense regimen, as compared to a more conventional protocol. However, our simulations suggest that a well tolerable continuous protocol is no less efficient. The results of the study provide insights into the effectivity of chemotherapy and may assist in designing better protocols.

A Subchronic Toxicity Study of Phosflex 51B in Sprague-Dawley Rats

2001 ◽  
Vol 20 (5) ◽  
pp. 269-274 ◽  
Author(s):  
Ralph I. Freudenthal ◽  
David Brandwene ◽  
Welmoed Clous
Keyword(s):  
Food Consumption ◽  
Clinical Chemistry ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Sprague Dawley ◽  
Significant Treatment ◽  
Sprague Dawley Rats ◽  
The Mean ◽  
Microscopic Pathology

Phosflex 51B is a flame retardant plasticizer that is blended with polyvinyl chloride films to effectively control product flammability. Its composition places it in the butylated triphenyl phosphate category. Previous studies have shown Phosflex 51B to have low acute toxicity, to lack teratogenic and mutagenic activity, and to not induce delayed peripheral neuropathy. The present study was conducted to determine the toxicity of Phosflex 51B after repeated dietary exposure. Four groups, each consisting of 20 male and 20 female Sprague-Dawley rats, received rodent diet containing either 0, 100, 400, or 1600 ppm for 90 days. Parameters measured include body weight, food consumption, clinical observations, hematology, clinical chemistry, and cholinesterase activity. Tissues were examined at necropsy for gross changes and were processed for microscopic pathology. There were no significant treatment-related effects on body weights, food consumption, hematology and clinical chemistry, or cholinesterase values. A significant increase was observed in the absolute and relative mean weights of livers in high-dose male rats, the mean relative fiver weights of the high-dose female animals, the mean relative kidney weights of the high-dose male rats, and the mean absolute weights of the adrenal glands from high-dose female rats. Neither gross nor microscopic pathology examinations revealed tissue changes in these organs or in any other organs. Although increases in fiver, kidney, and adrenal weights were observed in certain animals in the 1600-ppm high-dose group, the administration of Phosflex 51B did not result in significant treatment-related adverse effects at dietary dose levels of 100 and 400 ppm. The no-observable-effect level (NOEL) in this study is 400 ppm.

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