toremifene and Liver-Neoplasms

Multidrug resistance protein could be a target for improving the efficacy of paclitaxel (PXL). Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. Some P-gp moderators may change the pharmacokinetic parameters of PXL in vivo. A pharmacokinetic (PK) study in metastatic breast cancer patients (MBC) was conducted to determine the safety and efficacy of PXL and TOR.. Fifteen patients received 80 mg/m(2) PXL (i.v.) weekly and 120 mg/body TOR (p.o.) daily. For the pharmacokinetic study, PXL was administered on days 1, 8, 15, 32, and 39; TOR was given from day 18 to the end of study. On days 1, 8, 15, 18, 32, and 39, blood samples were collected from the patients who received either PXL alone or PXL + TOR, and these were analyzed by high-performance liquid chromatography.. Among the 15 patients enrolled in the study, one showed a partial response, and eight had a stable disease. TOR caused no specific adverse events that were greater than grade 3, and its toxicity profile in combination with PXL was similar to that of PXL monotherapy. The PK profile of PXL was similar with or without TOR. The PK parameters of PXL indicated no inter- or intra-patient variability in previously treated patients with MBC. No increased PXL toxicity was observed.. The PK profile of combined PXL and TOR was similar to that of PXL monotherapy. The addition of TOR to PXL in previously treated patients with MBC appears safe.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bone Neoplasms; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Staging; Paclitaxel; Prognosis; Survival Rate; Tissue Distribution; Toremifene; Treatment Outcome

A 5 6-year-old woman, who underwent breast-conserving surgery and radiation (60 Gy) therapy in July, 1992, at the age of 40, was diagnosed with pT1aN0M0, pStage I. She was administered tamoxifen (TAM) as adjuvant therapy. However, she underwent microdochectomy for DCIS in her contralateral breast in June, 1998. TAM was given till August, 1999. In June, 2006, at the age of 54, 14 years after initial surgery, CT revealed extensive liver masses which were diagnosed as liver metastasis by liver biopsy. Receptor status was positive for ER and PgR, and negative for HER2. AC was started as a first-line chemotherapy ( 4 courses), but did not prove effective. She refused second-line chemotherapy, so letrozole was selected, and subsequently resulted in PR of the liver metastasis. However, 8 months later, with a liver metastasis relapse, exemestane followed by tamoxifen, medroxyprogesterone acetate, and high-dose toremifene were administered sequentially, resulting in long-time disease control. In conclusion, endocrine therapy might be an effective option even in a visceral crisis, if metastatic tumors have showed slow growth and there is positive hormone receptor status.

Topics: Androstadienes; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Letrozole; Liver Neoplasms; Medroxyprogesterone; Middle Aged; Neoplasm Recurrence, Local; Nitriles; Tamoxifen; Toremifene; Triazoles

A 47-year-old woman was admitted to our hospital for advanced breast cancer with multiple liver metastases and liver dysfunction in January 2004. EC (EPI combined with CPA), weekly PTX, and AI were performed but were not effective for that tumor. Therefore, high-dose TOR was started. Liver dysfunction recovered after administration of TOR, and primary tumor and liver metastases were evaluated as a partial response (PR). The same therapy has been performed for six months with no evidence of deterioration.

Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Middle Aged; Nitriles; Quality of Life; Remission Induction; Toremifene; Triazoles

Female breast cancer is one of the major causes of death among women while male breast cancer is relatively uncommon and accounts for about 1% of all breast cancers in both sexes. Influencing factors are: gynecomasty, familiarity for male breast cancer, Jewish and African-American male population. From the histological point of view, it is not different from the female breast cancer, except for the infiltrant ductal carcinoma, but with a much severe prognosis. Breast cancer metastases to the jaws are rare, only 1%; the most common sites of metastases are: lungs(59-69%), liver (58-65%), bone (44-71%), pleura (23-37%), brain (9-22%) and kidney (4-17%). At present, based on a literature research (May 2006), there have been just two other case reports of male breast cancer metastasis to the maxillofacial region, both to the mandible. The case of a 69-year-old white man who in 2001 underwent a radical mastectomy due to ductal breast cancer is reported. In 2005 the patient was referred to our department by his oncologist for multiple oral fistula. A mandibular TC revealed osteolytic lesions and the patient underwent mandibular surgery to remove the lesions and clean up the area. The histological examination was consistent with that of a metastatic deposit of adenocarcinoma of the breast. In June 2006 the patient died due to worsening of the general clinical conditions, in particular due to ascites and hepatic insufficiency.

Topics: Aged; Androstadienes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms, Male; Carcinoma, Ductal, Breast; Cortisone; Cyclophosphamide; Diphosphonates; Docetaxel; Fatal Outcome; Fluorouracil; Furosemide; Humans; Imidazoles; Liver Neoplasms; Male; Mandibular Neoplasms; Mastectomy, Modified Radical; Methotrexate; Omeprazole; Osteolysis; Phenobarbital; Taxoids; Toremifene; Vinblastine; Vinorelbine; Zoledronic Acid

High-dose toremifene therapy (120 mg/day) is useful for the recurrence of receptor-positive breast cancer. However, some reports show that combination therapy of high-dose toremifene and chemotherapy exhibits additive effects. Twelve patients were given oral chemotherapy (capecitabine, 5'-DFUR+CPA, S-1) with high-dose toremifene. The overall response rate was 41.7%, in addition to 58.3% with no change beyond three months. Adverse events were restricted to headache, stomatitis and nausea. Average time to progressive (TTP) was 5.8 months. It was shown that high-dose toremifene and oral chemotherapy were useful for breast cancer recurrence without severe side effects.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Floxuridine; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Quality of Life; Skin Neoplasms; Tegafur; Toremifene

Intrahepatic transplantation of ovarian fragments in ovariectomized rats results in morphological abnormalities. The liver acini draining blood from ovarian grafts show alterations resembling chemically induced amphophilic hepatocellular preneoplasias. We investigated the long-term development of these estrogen-induced foci of altered hepatocytes (FAH). We divided 451 Lewis rats into one main group (MG) and 11 (7 female, 4 male) control groups and observed them for up to 30 months. MG animals were ovariectomized and received ovarian transplants into the right liver part. Different combinations of castration, transplantation of ovarian or testicular fragments, and administration of antiestrogenic toremifene were used in controls. In the MG, transplants showed signs of gonadotropic stimulation, and estrogen levels were strongly increased in the downstream liver acini. After 6 and 12 months, FAH developed in hepatocytes downstream of the transplants. After 18 months, 27% of the MG animals showed transformation of FAH into hepatocellular adenomas; this figure increased to 42% after 24 months (8/19), significantly outnumbering four spontaneous adenomas that developed between 18 and 30 months in 258 control animals. Hepatocellular carcinoma (HCC) appeared only in the MG. At 24 and 30 months, 18 HCCs developed; thus, 78% of MG animals showed at least one carcinoma. Administration of toremifene in ovariectomized and transplanted animals completely prevented hepatocarcinogenesis. Testicular grafts showed no influence on liver tissue. In conclusion, initially adaptive but preneoplastic alterations in hepatocytes downstream of intrahepatically transplanted ovarian fragments may transform into HCC, indicating a strong hepatocarcinogenic potential of high local levels of endogenous estrogens in the rat liver.

Topics: Adenoma, Liver Cell; Animals; Aorta; Carcinoma, Hepatocellular; Estradiol; Estrogen Antagonists; Estrogens; Female; Gonadal Steroid Hormones; Gonadotropins; Hepatic Veins; Hepatocytes; Immunohistochemistry; Liver; Liver Neoplasms; Male; Ovariectomy; Ovary; Precancerous Conditions; Rats; Rats, Inbred Lew; Testis; Toremifene; Transforming Growth Factor alpha; Transplantation, Heterotopic

A 36-year-old woman was admitted to our hospital because of general malaise in October 1999. She was diagnosed with bilateral breast cancer with bone marrow and liver metastases. Low-dose weekly paclitaxel (60 mg/body/week) combined with toremifene (120 mg/day) was started in December 1999. Myelofunction was recovered after 2 weeks of chemotherapy (CT), and the primary tumors and cervical/axillary lymphadenopathy disappeared after 4 weeks of CT. Bone marrow and liver metastases was no longer detected after 16 weeks of CT, and the case was evaluated as a complete response (CR). The same therapy has been performed for eight months and no evidence of recurrence has been observed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Liver Neoplasms; Paclitaxel; Remission Induction; Toremifene

We report a case of far advanced breast cancer showing an excellent response to chemo-endocrine therapy. A 40-year-old female with a huge ulcerated tumor on her left anterior chest visited our hospital. Distant metastases were found in the lymph nodes, liver and bone. Therefore, endocrine therapy (toremifene and medroxyprogesterone acetate) and chemotherapy (cyclophosphamide, Therarubicin and 5-fluorouracil) were started as a combination treatment. As a result, the main tumor and metastatic lesion were remarkably reduced, and extended mastectomy with resection of right axillary lymph nodes was performed. Histologically, cancer cells in the primary lesion mostly disappeared, and only one lymph node in the left axillary lesion showed metastasis. No recurrence was found for 16 months after the surgical treatment. The combined therapy in the present case was extremely effective.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Liver Neoplasms; Lymphatic Metastasis; Neoplasm Staging; Toremifene

A 68-year-old woman complained of obstructive jaundice 9 years after a radical mastectomy. CT scan demonstrated multiple metastasis of the liver and two coin lesions of the right lung. The biliary tract was completely obstructed at the portal fissure. Multiple liver and lung metastasis of breast cancer were diagnosed because of high CA 15/3 serum levels and normal gastrointestinal study. Following unsuccessful treatment with tamoxifen (TAM), we used toremifene (TORE) and 5'-deoxy-5-fluorouridine (5'-DFUR) followed by percutaneous transhepatic cholangiodrainage (PTCD). The biliary tract was reopening and jaundice disappeared with improvement of the general condition. Then endocrine therapy with medroxy progesterone acetate and UFT and chemotherapy with CAF (Cyclophosphamide, Adriamycin, 5-FU) were begun. A partial response (PR) was obtained with the disappearance of liver metastasis and two coin lesions of the lung 5 months after the first treatment. The effect of chemo-endocrine combination therapy continued for 5 months. Survival time from recurrence was 13 months. In our case, PR was obtained by using chemo-endocrine combination therapy, although a poor prognosis has been reported in patients with obstructive jaundice caused by multiple liver metastasis of recurrent breast cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cholestasis; Cyclophosphamide; Doxorubicin; Drainage; Female; Floxuridine; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Mastectomy, Radical; Medroxyprogesterone Acetate; Tamoxifen; Tegafur; Toremifene; Uracil

The antiestrogen tamoxifen is known to cause liver cancer in rats. This may be due to the formation of abundant DNA adducts in rat liver. A likely precursor to some of the tamoxifen adducts in rats is alpha-hydroxytamoxifen. It is not clear whether the rat data are relevant to human exposure. In the present study, we show that one of the major metabolites in humans reacts with double-stranded DNA in vitro in the absence of any metabolizing enzymes or activating chemicals. At least two distinct adduct spots resulting from 4-hydroxy-N-desmethyltamoxifen (metabolite Bx) were detected by 32P postlabeling and thin layer chromatography. The adduct level increases dramatically when metabolite Bx is irradiated with UV light to fuse into a phenanthrene ring system. 4-hydroxy-N-desmethyltoremifene, which differs from Bx by a single chlorine atom, forms fewer DNA adducts without irradiation but similar amounts after irradiation. These results suggest that the chlorine atom may interfere with drug-DNA interactions which facilitate adduct formation.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chromatography, Liquid; DNA Adducts; Female; Humans; In Vitro Techniques; Liver Neoplasms; Tamoxifen; Toremifene; Ultraviolet Rays

The hepatoproliferative effects of 2 antiestrogens, tamoxifen and toremifene, were compared in a sequential 15-month study in which 2 doses of each compound were administered by daily gavage to female Sprague-Dawley rats for up to 12 months. The doses were 11.3 and 22.6 mg/kg for tamoxifen and 12 and 24 mg/kg for toremifene. There were scheduled sacrifices at 3, 6, 12, and 15 months, the latter including a 3-month recovery period from the 12th through the 14th month. In the chronic toxicity study, tamoxifen at 22.6 mg/kg produced 100% incidence of hepatocellular carcinoma at the 12- and 15-month sacrifice intervals and 67% and 71% incidences at the 11.3-mg/kg dose. Sequential observations showed an increased incidence of glutathione S-transferase-positive foci of hepatocellular alteration by 3 months with tamoxifen in the absence of hepatotoxicity, with the first liver carcinoma appearing by 6 months of treatment. Unscheduled deaths occurring beyond 7.5 months in the tamoxifen treated groups were due in almost all cases to liver cancer. In striking contrast, toremifene did not produce any hepatoproliferative effects at 12- and 24-mg/kg dose levels, nor in a pilot study at 48 mg/kg. The 24-mg/kg dose of toremifene exerted an inhibiting effect on foci of hepatocellular alteration in rat liver detectable by glutathione S-transferase immunohistochemistry at 3 months and by conventional histology at 12 months. An antiproliferative effect was also evident in mammary gland and anterior pituitary where both toremifene and tamoxifen suppressed tumor incidence in comparison to the control group. The ability of these drugs to modify rat liver DNA after p.o. administration was investigated using the 32P-postlabeling assay. Administration of tamoxifen at 45 mg/kg for 7 days produced liver DNA nucleoside modifications represented by 7 spots on the autoradiogram. Unlike tamoxifen, toremifene did not produce any modified bases in rat liver DNA detectable by the 32P-postlabeling technique. The dose levels of tamoxifen that are strongly hepatocarcinogenic in the rat are compared with doses used in humans in various applications. Taking internal drug exposure into account, we conclude that the margin of safety for use of tamoxifen as an endocrine prophylactic agent for healthy, but breast cancer prone, women is questionable.

Topics: Adenoma; Animals; Carcinogens; Carcinoma, Hepatocellular; DNA; Female; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Tamoxifen; Toremifene