A RAY OF HOPE: A RAY OF HOPE: TAMOXIFENTAMOXIFEN

POWERPOINT PRESENTATION POWERPOINT PRESENTATION BYBY

NEIL RAKHOLIANEIL RAKHOLIAwww.tamoxi.tripod.comwww.tamoxi.tripod.com

OUTLINE:OUTLINE:TAMOXIFEN:A RAY OF HOPETAMOXIFEN:A RAY OF HOPE

1. TYPES OF BREAST CANCER1. TYPES OF BREAST CANCER A. DUCTAL CARCINOMAA. DUCTAL CARCINOMA B. LOBULAR CARCINOMAB. LOBULAR CARCINOMA C. INFLAMMATORY BREAST CANCERC. INFLAMMATORY BREAST CANCER2. RISK FACTORS2. RISK FACTORS A. OLDER AGEA. OLDER AGE B. PERSONAL/ FAMILY HISTORYB. PERSONAL/ FAMILY HISTORY C. HORMONE REPLACEMENT/ ALCOHOLC. HORMONE REPLACEMENT/ ALCOHOL D. EARLY MENARCHE/ NO CHILDREN/ CHILDREN AT LATE AGED. EARLY MENARCHE/ NO CHILDREN/ CHILDREN AT LATE AGE3. HORMONE THERAPY WITH TAMOXIFEN3. HORMONE THERAPY WITH TAMOXIFEN A.CHEMICAL STRUCTURE AND SYNTHESISA.CHEMICAL STRUCTURE AND SYNTHESIS B.GENERAL B.GENERAL i. MECHANISM OF ACTIONi. MECHANISM OF ACTION ii. SIDE EFFECTSii. SIDE EFFECTS C. INDICATION AND USAGE C. INDICATION AND USAGE i. METASTATIC BREAST CANCERi. METASTATIC BREAST CANCER ii. DUCTAL CARCINOMA IN SITUii. DUCTAL CARCINOMA IN SITU iii. PREVENTION IN HIGH RISK WOMENiii. PREVENTION IN HIGH RISK WOMEN D. FUTURE DIRECTIOND. FUTURE DIRECTION i. TAMOXIFEN AS PREVENTIVE MEASUREi. TAMOXIFEN AS PREVENTIVE MEASURE ii. BIPHOSPHONATESii. BIPHOSPHONATES iii. HERCEPTIN/ MONOCLONAL ANTIBODYiii. HERCEPTIN/ MONOCLONAL ANTIBODY

BREAST CANCER BREAST CANCER EPIDEMIOLOGY *EPIDEMIOLOGY *FDAFDA

• The National Cancer Institute estimates The National Cancer Institute estimates that 13.4 percent of women born today that 13.4 percent of women born today will be diagnosed with breast cancer at will be diagnosed with breast cancer at some time in their livessome time in their lives

• In 1070’s risk of getting breast cancer In 1070’s risk of getting breast cancer was “1 in 10”, now it is “1 in 7”was “1 in 10”, now it is “1 in 7”

• This increase in risk may be due to This increase in risk may be due to better diagnostic tests, increase in age, better diagnostic tests, increase in age, changes in life stylechanges in life style

TYPES AND RISK FACTORS OF TYPES AND RISK FACTORS OF BREAST CANCER *BREAST CANCER *NEJMNEJM

• DUCTAL DUCTAL CARCINOMACARCINOMA

• LOBULAR LOBULAR CARCINOMACARCINOMA

• INFLAMMATORY INFLAMMATORY BREAST CANCERBREAST CANCER

• OLDER AGEOLDER AGE• STARING PERIOD AT STARING PERIOD AT

EARLY AGEEARLY AGE• OLDER AGE AT OLDER AGE AT

FIRST CHILD OR NO FIRST CHILD OR NO CHILDCHILD

• FAMILY HISTORYFAMILY HISTORY• ALCOHOL/ ALCOHOL/

HORMONE USEHORMONE USE• BEING WHITEBEING WHITE

TREATMENT 0F BREAST TREATMENT 0F BREAST CANCER *CANCER *BARRBARR

THERE ARE FOUR MAJOR TYPES TREATMENT IS THERE ARE FOUR MAJOR TYPES TREATMENT IS USED USED

SURGERYSURGERY• RADIATIONRADIATION• HORMONE THERAPYHORMONE THERAPY• CHEMOTHERAPYCHEMOTHERAPY TAMOXIFEN IS CONSIDERED AS NON-STEROIDAL TAMOXIFEN IS CONSIDERED AS NON-STEROIDAL

ANTI ESTROGENANTI ESTROGENIT BLOCKS THE ESTROGEN FROM BINDING TO IT BLOCKS THE ESTROGEN FROM BINDING TO

THE CANCERCELLS AND THUS INHIBITING THE CANCERCELLS AND THUS INHIBITING THEIR GROWTHTHEIR GROWTH

SYNTHESISSYNTHESIS• I. SHIINA AND M. SUZUKI APPROCHED THE I. SHIINA AND M. SUZUKI APPROCHED THE

SYNTHESIS OF TAMOXIFEN BY TETRASUBSTITUTED SYNTHESIS OF TAMOXIFEN BY TETRASUBSTITUTED ALKENE CORE OF TAMOXIFEN BY SUCCESIVE ALKENE CORE OF TAMOXIFEN BY SUCCESIVE ALLYYLATION OF AROMATIC ALDEHYDES AND A ALLYYLATION OF AROMATIC ALDEHYDES AND A FRIEDEL-CRAFTS ALKYLATION, FOLLOWED BY FRIEDEL-CRAFTS ALKYLATION, FOLLOWED BY MIGRATION OF DOUBLE BOND. THE STARTEGY MIGRATION OF DOUBLE BOND. THE STARTEGY WAS TYPICALLY CARRIED OUT AS A 3 COMPONENT WAS TYPICALLY CARRIED OUT AS A 3 COMPONENT COUPLING REACTION AMONG COUPLING REACTION AMONG BENZALDEHYDE,CINNAMYLTRIMETHYLSILANE AND BENZALDEHYDE,CINNAMYLTRIMETHYLSILANE AND ANISOLE WITH HfCL4 AND ANISOLE WITH HfCL4 AND TRIMETHYLSILYLTRIFLUOROMETHANESULFONATETRIMETHYLSILYLTRIFLUOROMETHANESULFONATE

INDICATION/USES AND SIDE INDICATION/USES AND SIDE EFFECTS of TAMOXIFENEFFECTS of TAMOXIFEN• METASTATIC BREAST METASTATIC BREAST

CANCERCANCER• ADJUVENT TREATMENT OF ADJUVENT TREATMENT OF

BREAST CANCERBREAST CANCER• DUCTAL CARCINOMA IN DUCTAL CARCINOMA IN

SITUSITU• MCCUNE-ALBRIGHT MCCUNE-ALBRIGHT

SYNDROMESYNDROME• REDUCTION IN INCIDENCE REDUCTION IN INCIDENCE

OF HIGH RISK PATIENTSOF HIGH RISK PATIENTS

• DISCHARGE HOT FLASHES, DISCHARGE HOT FLASHES, VAGINAL, MENSTRUAL VAGINAL, MENSTRUAL IRREGULARITIES, HAIR IRREGULARITIES, HAIR LOSS, SKIN CHANGES, SKIN LOSS, SKIN CHANGES, SKIN RASHES, HEADACHE, RASHES, HEADACHE,

• BLOOD CLOTS IN THE BLOOD CLOTS IN THE VEINSVEINS

• ENDOMETRIAL CANCERENDOMETRIAL CANCER• STROKESTROKE

NSABP B-24 TRIAL PRIMARY OBJECTIVE IS TO NSABP B-24 TRIAL PRIMARY OBJECTIVE IS TO DETERMINE IF TAMOXIFEN REDUCE INCIDENCE OF DETERMINE IF TAMOXIFEN REDUCE INCIDENCE OF RECURRANCE RECURRANCE

TYPE OF EVENTTYPE OF EVENT LUMPACTOMY,RADIOLUMPACTOMY,RADIOTHERAPY AND THERAPY AND PLACEBOPLACEBO#EVENTS PER #EVENTS PER 10001000

LUMPACTOMY, LUMPACTOMY, RADIOTHERAPY RADIOTHERAPY AND AND TAMOXIFENTAMOXIFEN

RELATIRELATIVE RISKVE RISK

INVASIVE INVASIVE BREAST BREAST CANCERCANCER

74 16.7374 16.73 44 9.6044 9.60 0.570.57

IPSILATERALIPSILATERAL 47 10.6147 10.61 27 5.9027 5.90 0.560.56CONTRALATERCONTRALATERALAL

25 5.6425 5.64 17 3.7117 3.71 0.660.66

SECONDARY SECONDARY END POINTSEND POINTSDCISDCIS 56 12.6656 12.66 41 8.9541 8.95 0.710.71IPSILATERALIPSILATERAL 46 10.4046 10.40 38 8.2938 8.29 0.880.88CONTRALATERCONTRALATERALAL

10 2.2610 2.26 03 0.6503 0.65 0.290.29

UTERINE UTERINE MALIGNANCIESMALIGNANCIES

0404 0909 2.252.25

MECHANISM OF ACTION AND MECHANISM OF ACTION AND SYNTHESISSYNTHESIS• TAMOXIFEN ACTS AS AN ANTI TAMOXIFEN ACTS AS AN ANTI

ESTROGENESTROGEN• IT BINDS TO THE BREAST CANCER IT BINDS TO THE BREAST CANCER

CELLS COMPETITIVELY TO THE CELLS COMPETITIVELY TO THE ESTROGENESTROGEN

• ESTROGEN STIMULATES THE ESTROGEN STIMULATES THE GROWTH OF THE TUMOR AND GROWTH OF THE TUMOR AND TAMOXIFEN INHIBITS THE GROWTH TAMOXIFEN INHIBITS THE GROWTH OF THE TUMOROF THE TUMOR

FUTURE DIRECTIONFUTURE DIRECTION• BREAST CANCER IS A SECOND LEADING BREAST CANCER IS A SECOND LEADING

CAUSE OF DEATH IN AMERICAN WOMEN CAUSE OF DEATH IN AMERICAN WOMEN AND ACCOUNTS FOR 31 PERCENT OF AND ACCOUNTS FOR 31 PERCENT OF ALL CANCER IN WOMENALL CANCER IN WOMEN

• IN 1998, FDA APPROVED TAMOXIFEN AS IN 1998, FDA APPROVED TAMOXIFEN AS PREVENTIVE DRUG FOR HIGH RISK PREVENTIVE DRUG FOR HIGH RISK WOMENWOMEN

• TAMOXIFEN IS IN THE MARKET FOR TAMOXIFEN IS IN THE MARKET FOR OVER 20 YEARS OVER 20 YEARS

FUTURE DIRECTIONFUTURE DIRECTION• HECEPTIN (TRASTUZUMAB)HECEPTIN (TRASTUZUMAB)• MONOCLONAL GROWTH FACTOR MONOCLONAL GROWTH FACTOR

ANTIBODYANTIBODY• ZOLONDRONATE DOES KILL THE ZOLONDRONATE DOES KILL THE

CANCER CELLS?CANCER CELLS?

BIBLIOGRAPHYBIBLIOGRAPHY• http://www.nsabp.pitt.edu/B-24.htmhttp://www.nsabp.pitt.edu/B-24.htm• http://www.fda.gov/cder/news/tamoxifen/default.htmhttp://www.fda.gov/cder/news/tamoxifen/default.htm• http://www.chemistry.org/portal/a/c/s/1/http://www.chemistry.org/portal/a/c/s/1/

acsdisplay.html?DOC=heartcut%5carchiveacsdisplay.html?DOC=heartcut%5carchive%5c020904_heartcut.html#3%5c020904_heartcut.html#3

• http://www.chemistry.org/portal/a/c/s/1/http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=heartcut%5carchiveacsdisplay.html?DOC=heartcut%5carchive%5c020904_heartcut.html#3%5c020904_heartcut.html#3

• http://www.moffitt.usf.edu/pubs/ccj/v6n3/dept1.htmhttp://www.moffitt.usf.edu/pubs/ccj/v6n3/dept1.htm• http://www.nejm.orghttp://www.nejm.org• http://www.barrlabs.com/packageinserthttp://www.barrlabs.com/packageinsert