clozapine and Breast-Neoplasms

Breast cancer is more common in female patients with schizophrenia than in the general population. It is not known whether treatment with prolactin-increasing antipsychotics contributes to increased odds of breast cancer.. We used Finnish nationwide registers of hospital treatment, prescription drug purchases, and cancer diagnoses to do a nested case-control study. Of women with schizophrenia, those with breast cancer (cases) were matched by age and duration of illness with five women without cancer (controls). Cases and controls were aged 18-85 years and exclusion criteria were any previous cancer diagnoses, receipt of organ transplant, mastectomy, or diagnosis of HIV. The main analysis was the association between cumulative exposure to prolactin-increasing drugs and breast cancer. The analyses were done with conditional logistic regression, by adjusting for comorbid conditions and concomitant medications. Ethnicity data were not available.. Of 30 785 women diagnosed with schizophrenia between 1972 and 2014, 1069 were diagnosed with breast cancer between Jan 1, 2000, and Dec 31, 2017. Compared with 5339 matched controls, 1-4 years cumulative exposure (adjusted odds ratio [OR] 0·95, 95% CI 0·73-1·25) or 5 or more years exposure (adjusted OR 1·19, 0·90-1·58) to prolactin-sparing antipsychotics (including clozapine, quetiapine, or aripiprazole) was not associated with an increased risk of breast cancer in comparison with minimal exposure (<1 year). When compared with less than 1 year of exposure to prolactin-increasing antipsychotics (all other antipsychotics), 1-4 years of exposure was not associated with an increased risk, but exposure for 5 or more years was associated with an increased risk (adjusted OR 1·56 [1·27-1·92], p<0·001). The risk for developing lobular adenocarcinoma associated with long-term use of prolactin-increasing antipsychotics (adjusted OR 2·36 [95% CI 1·46-3·82]) was higher than that of developing ductal adenocarcinoma (adjusted OR 1·42 [95% CI 1·12-1·80]).. Long-term exposure to prolactin-increasing, but not to prolactin-sparing, antipsychotics is significantly associated with increased odds of breast cancer. Monitoring prolactinemia and addressing hyperprolactinemia is paramount in women with schizophrenia being treated with prolactin-increasing antipsychotics.. Finnish Ministry of Social Affairs and Health.

Topics: Adult; Aged; Antipsychotic Agents; Breast Neoplasms; Carcinoma, Lobular; Case-Control Studies; Clozapine; Female; Finland; Humans; Middle Aged; Prolactin; Quetiapine Fumarate; Schizophrenia

We recently reported alkoxyl biphenyl derivatives bearing dibenzo[c,e]azepine scaffold as novel P-glycoprotein (P-gp, ABCB1) inhibitors. In this study, their ability to reverse breast cancer resistance protein (BCRP, ABCG2)-mediated multidrug resistance was tested in HEK293/BCRP cells which was BCRP-transfected stable HEK293 cells. It was observed that compounds 4d, 4h, 4i increased mitoxantrone accumulation in HEK293/BCRP cells via inhibiting BCRP efflux function. Notably, the inhibitory activity of 4i was comparable to that of the classical BCRP inhibitor Ko143 at an equimolar concentration. Interestingly, 4i had little inhibitory effect on multidrug resistance-associated protein 1 (MRP1, ABCC1), another drug efflux transporter. These results, together with the previous findings, suggest that 4i may be a dual inhibitor of P-gp and BCRP to warrant further investigation.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Clozapine; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Neoplasm; Female; HEK293 Cells; Humans; Molecular Structure; Neoplasm Proteins; RNA, Messenger; Structure-Activity Relationship

The presence of the histamine H₄ receptor (H₄R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H₄R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model.. Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H₄R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹).. Data indicate that developed tumours were highly undifferentiated, expressed H₄R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H₄R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis.. Histamine through the H₄R exhibits a crucial role in tumour progression. Therefore, H₄R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Clozapine; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Histamine; Histamine Agonists; Humans; Indoles; Mice; Mice, Nude; Oximes; Proliferating Cell Nuclear Antigen; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Survival Rate; Xenograft Model Antitumor Assays

Topics: Adult; Antineoplastic Agents; Antipsychotic Agents; Bleomycin; Breast Neoplasms; Carcinoma; Cisplatin; Clozapine; Etoposide; Female; Humans; Intestinal Neoplasms; Male; Middle Aged; Neoplasms; Neutropenia; Schizophrenia; Seminoma; Testicular Neoplasms

Topics: Agranulocytosis; Antibiotics, Antineoplastic; Antipsychotic Agents; Breast Neoplasms; Clozapine; Doxorubicin; Female; Humans; Middle Aged; Neutropenia; Schizophrenia