mercaptopurine and Breast-Neoplasms

Topics: Age Factors; Breast Neoplasms; Cell Movement; Clinical Enzyme Tests; Colonic Neoplasms; Cytarabine; Diagnosis, Differential; Doxorubicin; Drug Combinations; Drug Evaluation; Drug Evaluation, Preclinical; Fluorouracil; Humans; Kinetics; Leukemia; Mercaptopurine; Methods; Methotrexate; Models, Chemical; Neoplasms; Prognosis; Sarcoma; Testosterone; Thioguanine

Topics: Adrenal Cortex Hormones; Alkaloids; Alkylating Agents; Androgens; Antimetabolites; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Cytosine; Estrogens; Fluorouracil; Hormones; Humans; Mercaptopurine; Methotrexate; Mitomycins; Neoplasm Recurrence, Local; Nitrogen Mustard Compounds; Thiotepa

BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumour cells with these mutations demonstrate increased sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin. Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers.. This multi-centre phase II single arm trial was designed to investigate the activity and safety of 6-mercaptopurine (6MP) 55 mg/m² per day, and methotrexate 15 mg/m² per week in patients with advanced breast or ovarian cancer, ECOG PS 0-2, progressing after ≥ one prior regimen and known to bear a BRCA1/2 germ line mutation. Accrual was planned in two stages, with treatment continuing until progression or unacceptable toxicity; in the first, if less than 3/30 evaluable patients respond at 8 weeks after commencing treatment, the trial will be stopped for futility; if not, then accrual would proceed to a second stage, in which if more than 9/65 evaluable patients are found to respond at 8 weeks, the treatment will be regarded as potentially effective and a phase III trial considered subject to satisfactory safety and tolerability. The primary outcome is objective response at 8 weeks, defined by RECISTS v1.1 as complete response, partial response or stable disease. Secondary outcomes include safety, progression- free and overall survival, and quality of life.. This study aims to investigate whether 6MP might be an effective treatment for BRCA deficient tumours even after the development of resistance to PARP inhibitors or platinum drugs. The study has surpassed the first stage analysis criteria of more than 3 out of 30 evaluable patients responding at 8 weeks, and is currently in the second stage of recruitment.. NCT01432145 http://www.ClinicalTrials.gov.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Protocols; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Mercaptopurine; Methotrexate; Ovarian Neoplasms

Topics: Breast Neoplasms; Clinical Trials as Topic; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Lymphoma; Melanoma; Mercaptopurine; Neoplasms

Topics: Aged; Antimetabolites; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Genotype; Humans; Mercaptopurine; Middle Aged; Precision Medicine; Tamoxifen

Breast cancer recurrence may be promoted by immunosuppression due to decreased immune surveillance. The aim of this study was to examine the rates of breast cancer recurrence in patients with immune-mediated disease and treated breast cancer who received therapy with methotrexate, thiopurines, or anti-tumor necrosis factor (anti-TNF).. Three retrospective cohort studies within Medicare (2000-2012) included women with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) who underwent surgery for primary breast cancer. Recurrent or second primary breast cancers occurring more than 365 days after the initial surgery were identified. Separate Cox regression models were used to examine the risk of cancer recurrence in patients treated with methotrexate, thiopurines, or anti-TNF agents after surgery, each compared with no use. Analyses were matched for type of breast surgery and receipt and type of adjuvant therapy.. Across all medication groups, 107 women experienced breast cancer recurrence during 5,196 person-years. The incidence rates were 20.3 and 19.6 per 1,000 person-years in methotrexate users and nonusers, respectively, 32.3 and 17.6 in thiopurine users and nonusers, respectively, and 22.3 and 19.5 in anti-TNF users and nonusers, respectively. There was no significantly increased risk of breast cancer recurrence with use of methotrexate (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.67-1.69), anti-TNF therapy (HR 1.13, 95% CI 0.65-1.97), or thiopurines (HR 2.10, 95% CI 0.62-7.14).. The risk of breast cancer recurrence in patients who received methotrexate, thiopurine, or anti-TNF therapy was not statistically significantly increased, although we cannot rule out a 2-fold or greater increased risk in those treated with thiopurines. These data provide reassurance to clinicians choosing to start methotrexate or anti-TNF therapy in RA or IBD patients with treated breast cancer.

Topics: Adalimumab; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Azathioprine; Breast Neoplasms; Cohort Studies; Etanercept; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Infliximab; Medicare; Mercaptopurine; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tumor Necrosis Factor-alpha; United States

Topics: Aged, 80 and over; Antibodies, Bispecific; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Breast Neoplasms; Carcinoma, Transitional Cell; Cytarabine; Female; Humans; Lymphoma, B-Cell; Mercaptopurine; Methotrexate; Neoplasms, Second Primary; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Salvage Therapy; Urinary Bladder Neoplasms; Vincristine

Our study showed that a combination of 6-thiopurine (6-TP) drugs and a redox agent effectively inhibits the motility of SUM cells derived from human inflammatory breast cancer (IBC) cells and RhoC-overexpressed mammary epithelium cells. This 6-TP-mediated inhibition of cell motility occurs because the treated 6-TPs target and inactivate RhoC. A molecular mechanism for inactivation by the 6-TP-mediated RhoC is proposed by which treated TPs are converted in cells into 6-thioguanosine phosphate (6-TGNP). This 6-TGNP in turn reacts with the Cys(20) side chain of the redox-sensitive GXXXCGK(S/T)C motif of RhoC to produce a 6-TGNP-RhoC disulfide adduct. A redox agent synergistically enhances the formation process of this disulfide. The adduct that is formed impedes RhoC guanine nucleotide exchange, which populates an inactive RhoC. Our results suggest that 6-TGNP can also react with the redox-sensitive GXXXCGK(S/T)C and GXXXXGK(S/T)C motif of RhoA and Rac, respectively, to produce a 6-TGNP-RhoA and 6-TGNP-Rac disulfide adduct. However, given that RhoC has been shown to be overexpressed in ∼90% of IBC lesions, the populated RhoC but not other Rho proteins is likely to be a primary target for 6-TPs and a redox agent to terminate the metastasis of IBC.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Migration Inhibition; Crystallography, X-Ray; Drug Delivery Systems; Drug Synergism; Female; Gene Silencing; Guanine Nucleotides; Humans; Inflammation Mediators; Mercaptopurine; Neoplasm Invasiveness; Oxidation-Reduction; Prodrugs; rho GTP-Binding Proteins; rhoC GTP-Binding Protein; Thionucleotides

We have studied the potential contribution of ABCG2 (breast cancer resistance protein) to resistance to nucleoside analogues. In cells transfected with DNA constructs resulting in overexpression of human or mouse ABCG2, we found resistance against cladribine, clofarabine, fludarabine, 6-mercaptopurine, and 6-mercaptopurine riboside in both MDCKII and HEK293 cells and against gemcitabine only in HEK293 cells. With Transwell studies in MDCK cells and transport experiments with vesicles from Sf9 and HEK293 cells, we show that ABCG2 is able to transport not only the nucleotide CdAMP, like several other ATP-binding cassette transporters of the ABCC (multidrug resistance protein) family, but also the nucleoside cladribine itself. Expression of ABCG2 in cells results in a substantial decrease of intracellular CdATP, explaining the resistance against cladribine. The high transport rate of cladribine and clofarabine by ABCG2 deduced from Transwell experiments raises the possibility that this transporter could affect the disposition of nucleoside analogues in patients or cause resistance in tumors.

Topics: Adenine Nucleotides; Adenosine Monophosphate; Animals; Antineoplastic Agents; Arabinonucleosides; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Breast Neoplasms; Cell Line; Cladribine; Clofarabine; Dogs; Drug Resistance, Neoplasm; Gene Expression Regulation; Humans; Mercaptopurine; Mice; Neoplasm Proteins; Nucleosides; RNA, Messenger; Transfection; Transport Vesicles

Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.. A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.. A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.. In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Breast Neoplasms; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Intestinal Neoplasms; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Neoplasms; Risk Factors; Time Factors

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Female; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Drug screening trials and general treatment of solid tumours in advanced cancer patients have been concerned only with the site of primary origin, regardless of where metastases might have seeded. Since the environment for tumour growth can differ appreciably at various anatomical sites, an investigation was undertaken to determine the effect of metastatic site on response to chemotherapy. Data from 1961 to 1965 of the screening trials of the Eastern Clinical Drug Evaluation Program were utilized. Response and location data extensive enough for analysis represented 6 sites of primary origin and 6 metastatic site groups, totalling 1687 lesions. Analysis of percentage reduction in tumour size after chemotherapy regimens of up to 60 days revealed a significant amount of variation associated with metastatic sites and a non-significant amount associated with sites of primary origin. Advanced primary tumours showed marked variation in responsiveness and some showed a difference in response to different drug groups. Generally, metastases responded better than the advanced primaries from which they were derived, except for those from breast tumours.

Topics: Antineoplastic Agents; Breast Neoplasms; Chlorambucil; Female; Fluorouracil; Genital Neoplasms, Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Melanoma; Mercaptopurine; Mitomycins; Neoplasm Metastasis; Neoplasms

Topics: Abdominal Neoplasms; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Gallbladder Neoplasms; Hodgkin Disease; Humans; Kidney Neoplasms; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Mercaptopurine; Middle Aged; Pancreatic Neoplasms; Prednisolone; Rectal Neoplasms; Stomach Neoplasms; Ultrasonography; Vincristine

Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Autopsy; Azathioprine; Brain; Breast Neoplasms; Female; Hodgkin Disease; Humans; Immunosuppression Therapy; Infection Control; Infections; Kidney Transplantation; Lung; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Middle Aged; Myocardium; Neoplasm Metastasis; Prednisone; Toxoplasmosis; Transplantation, Homologous

Topics: Acute Disease; Adolescent; Adult; Age Factors; Biopsy, Needle; Breast Neoplasms; Child; Cytarabine; Daunorubicin; Diagnosis, Differential; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Menarche; Mercaptopurine; Methotrexate; Prednisolone; Sulfates; Vincristine

Topics: Adult; Asparaginase; Breast Neoplasms; Cecal Diseases; Child; Cytarabine; Daunorubicin; Female; Fluorouracil; Humans; Intestinal Perforation; Leukemia; Male; Mercaptopurine; Methotrexate; Middle Aged; Necrosis; Prednisone; Thioguanine; Vincristine

Topics: Adolescent; Adult; Breast Neoplasms; Citrates; Female; Gallium; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Nasopharyngeal Neoplasms; Prednisone; Radionuclide Imaging; Vincristine

Topics: Adult; Amines; Breast Neoplasms; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Imidazoles; Mercaptopurine; Methotrexate; Middle Aged; Mitomycins; Neoplasm Metastasis; Prednisone; Triazines; Vincristine

Topics: Amines; Antineoplastic Agents; Azirines; Azo Compounds; Breast Neoplasms; Caproates; Carbohydrates; Chlorambucil; Cyclophosphamide; Evaluation Studies as Topic; Floxuridine; Fluorouracil; Humans; Imidazoles; Mercaptopurine; Methotrexate; Mitomycins; Palliative Care; Prednisone; Triazines; Vincristine

Topics: Animals; Breast Neoplasms; Carcinoma; Cell Transformation, Neoplastic; Cyclophosphamide; Disease Models, Animal; DNA Replication; Female; Humans; Leukemia; Lymph Nodes; Mercaptopurine; Mice; Neoplasm Metastasis; Sarcoma

Topics: ABO Blood-Group System; Absorption; Adenocarcinoma; Antineoplastic Agents; Blood Platelets; Breast Neoplasms; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Dysgerminoma; Erythrocytes; Female; Hemagglutination Tests; Humans; Immune Sera; Isoantigens; Leukemia; Leukocytes; Male; Mercaptopurine; Methotrexate; Nitrogen Mustard Compounds; Pregnancy; Uracil Mustard

Topics: Breast Neoplasms; Cobalt Isotopes; Cyclophosphamide; Dactinomycin; DNA, Neoplasm; Female; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Prednisone; Radiotherapy Dosage; RNA, Messenger; Testicular Neoplasms

Topics: Antineoplastic Agents; Breast Neoplasms; Colonic Neoplasms; Cytarabine; Female; Fluorouracil; Humans; Lung Neoplasms; Mercaptopurine; Methotrexate; Neoplasms; Prognosis; Time Factors

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Drug Synergism; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Injections, Intramuscular; Injections, Intravenous; Lectins; Lung Neoplasms; Mechlorethamine; Mercaptopurine; Methotrexate; Mouth Neoplasms; Neoplasm Metastasis; Pharyngeal Neoplasms; Urogenital Neoplasms; Vinblastine

Topics: Breast Neoplasms; Child; Child, Preschool; Follow-Up Studies; Humans; Leukemia, Lymphoid; Mercaptopurine; Prognosis

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Scirrhous; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Squamous Cell; Culture Techniques; Flavonoids; Fluorouracil; HeLa Cells; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methods; Mitomycins; Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Anti-Bacterial Agents; Breast Neoplasms; Carcinoma; Female; Fluorouracil; Humans; Leukemia, Myeloid; Lymphatic Metastasis; Mastectomy; Mercaptopurine; Methotrexate; Middle Aged

Topics: Antineoplastic Agents; Breast Neoplasms; Cobalt Isotopes; Cyclophosphamide; Female; Fluorouracil; Humans; Mercaptopurine; Radioisotope Teletherapy

Topics: Animals; Breast Neoplasms; Cyclophosphamide; Female; Folic Acid Antagonists; Mercaptopurine; Mice

Topics: Animals; Breast Neoplasms; Carcinogens; Cyclophosphamide; Dactinomycin; Diet; Diet Therapy; Humans; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mechlorethamine; Mercaptopurine; Methotrexate; Methylcholanthrene; Neoplasms; Rats; Research; Toxicology

Topics: Antigen-Antibody Reactions; Biomedical Research; Blood Group Antigens; Breast Neoplasms; Colonic Neoplasms; Escherichia coli; Francisella tularensis; gamma-Globulins; Humans; Melanoma; Mercaptopurine; Neoplasms; Pharmacology; Placebos; Skin Tests; Skin Transplantation; Transplantation Immunology

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Cortisone; Humans; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Puromycin; Research; Sarcoma 180; Uracil Mustard; Zymosan