2011 07 Pharmacology Chemotherapy for Cancer

Subject: Pharmacology Topic: Chemotherapy/ Anti-Neoplastic  Agents Lecturer: Dr. Paul Dexter Santos Date of Lecture: July 20, 2011 Transcriptionist: Teriyaki, Sushi and Brewed Coffee Pages: 10 Outline I.

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Cytotoxic agent a. Alkylating agents b. Anti-metabolites c. Platinums d. Tumor antibiotics e. Anti-mitotic agents Hormonal Treatment a. Anti-Estrogens b. GnRH agonists c. Androgen receptor blockers Biologic Response Modifiers a. Interleukin b. G-CSF Targeted Agents a. Monoclonal antibodies b. Tyrosine kinase inhibitors

II.

III.

IV.

CANCER A disease characterized by an abnormal and uncontrolled proliferation of cells which can metastasize or spread (the difference from neoplasia, the aspect of metastasis) Triggered by an interplay of genetic and environmental factors

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Solid tumors have a slower growth rate (longer Td) compared to a hematologic cancer (2-3 mos. Vs 24 hrs) Ex: Lung cancer grows slower than leukemia

Why do solid tumors have longer double time than hematologic cancers? Solid tumors have a basement membrane and an extracellular matrix which limits spread. Compared to hematologic, which has no limiting barriers to growth in the blood. Therapy is most effective in the stage where tumor burden is low, but growth rate is high. Once it plateaus on the logarithmic scale, then it is very difficult to treat *You'd like to catch the cancer in the 10^9 stage, this is when they are more treatable. The growth rate is the factor which makes it t reatable or not.

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drug therapy  Primary chemotherapy: administered as the primary treatment with no alternative treatment (NHL, SCLCA, Wilm’s) Adjuvant chemotherapy: drug therapy given after a definitive treatment, (whether surgery or  RT) Neoadjuvant chemotherapy: drug treatment  given before a definitive treatment  They found out during the first world war that mustard gas is an irritant to skin, eyes and respiratory tract. Induced leukopenia, bone marrow, aslasia, and dissolution of lymphoid tissue. The mother of all chemotherapy is CYTOTOXIC. Difficulty in giving chemotherapy drugs is that there is an effective dose (the minimum dosing that you can have a beneficial effect of the host) while the toxic dose, where if you go to t he upper limit.

Logarithmic Growth of Cancer Cells 9

10 (a billion cancer) will produce a 1 cm tumor What symptom will that produce? In lungs? Nothing, no cough no weight loss Midbrain? Paralysis Breast? Nothing. It cannot be palpated; will not show up in ultrasound or mammogram 12 10 cancer cells will result in death of the host or patient •

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Tumor Doubling Time time it takes for a tumor to double its mass o

Cytotoxic drugs therapeutic window is very narrow compared to other drugs. A lot of cytotoxic drugs would entail giving a toxic dose for meaningful response to be achieved. Another rationale is that normal cells would recover more faster than the cancer cells. Thats why we permit the toxicity in order to eradicate the cancer cell in hopes the normal cell recovers. Chemotherapy comes in cycles (rest for three weeks and give another cycle). Leukopenia is a side effect of therapy. Once the bone marrow is fully recovered you can start again with another cycle. That is the rationale behind cycling of  chemotherapy.

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Cancer treatment agents CYTOTOXIC AGENTS [kill everything] 1. Alkylating Agent Nitrogen mustard 2. Antimetabolites Folic acid analogs: methotrexate Pyrimidine analogs: 5-FU Purine analogs:Mercaptopurin analogs:Mercaptopurine e 3. Anti-Mitotic Agents Vinca alkaloids and taxanes Phase Non-specific* Alkylating Agents o Platinum Compounds o Tumor Antibiotics

Phase Specific

Cytarabine Hydroxyurea o (Synthesis) Methotrexate o 6-Mercap o Vinca's And o Taxanes (Mitosis) *Can kill any part of the cell cycle o

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alkyltransferase (for nitrosoureas) Increased aldehyde dehydrogenase enzyme (inactivates cyclophosphamide) Bcl-2 over expression (anti-apoptotic gene) *If you're undergoing chemotherapy with an alkylating agent you minimize the use of  antioxidants and glutathione or other antioxidants. Toxicities Hematopoietic: Dose limiting toxicity Affects granulocytes and platelets affects every dividing cell in body RBCs, WBCs, Platelets, Bone marrow, Hair (that's why some chemotherapy drugs can induce a hair loss-alopecia) Gastrointestinal toxicity: nausea and vomiting less than the platinums (that's why you vomit, have abdominal pain, diarrhea) Gonadal toxicity: germ cell depletion without damaging sertoli cells. Oligospermia, aspermia, amenorrhea sperm cells are shielded by blood-testes barrier, but some can pass through the barrier. But not enough to induce complete sterility Pulmonary toxicity: busulfan, pneumonia like symptoms Teratogenicity (15% risk of malformation if  given in the first trimester) Carcinogenesis: in the long term you may have an increased risk of developing a secondary cancer Carcinogenesis: acute leukemia in about 5%. More common in melphalan vs cyclophosphamide Immunosuppression •

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1. MECHLORETHAMINE MECHLORETHAMINE (aka Mustargren) First original nitrogen mustard causes a bifunctional alkylation given IV *Always make sure the IV line is flowing well. you can run the risk of extravasation (meaning the drug is going outside blood vessel into subcutaneous tissue). The necrosis will be severe and requires plastic surgery for it to resolve. Rapidly undergoes transformation Part of the primary MOPP regimen for Hodgkin’s Lymphoma (Mustargen, Vincristine/Oncovin, Prednisone, Procarbazine) Dose 6mg/m2 on day 1, 8, monthly Subcutaneous extravasation should be avoided as this may cause severe necrosis • • •

ALKYLATING AGENTS TARGETS DNA Reacts with or ‘alkylates’ electron bridge atoms in the cells (electrophile characteristics) FORMS COVALENT BONDS WITH DNA COMPONENETS (usually N-7 of guanine) Monofunctional: reacts with one strand of  DNA Bifunctional: reacts with two strands of  DNA forming a cross-link THESE ABNORMALITIES IN THE DNA ARE DETECTED BY THE REPAIR SYSTEM THAT CAN LEAD TO CELL CYCLE ARREST OR APOPTOSIS (REQUIRES A P53 SYSTEM, GUARDIAN OF THE CELL) • •

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Mechanism Of Resistance Inactivation by other electron-rich molecules within the cell: Glutathione Repair of DNA damage that the agents produce: enzyme O6-alkylguanine•

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autoimmune disease orally administered

6. BUSULFAN Characteristic toxicity: VENOCCLUSIVE DISEASE OF THE LIVER (VOD) AT HIGH DOSES cross-links DNA both oral and IV administration presently used in high-dose therapy in conjunction with BMT: 16mg/kg (for CML) •

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Severe necrosis from extravasation

7. NITROSOUREAS Think of CNS Cross BBB  Alkylation at O6 guanine •

2. CYCLOPHOSPHAMIDE Presently, most widely used alkylating agent Bifunctional alkylates Can be given IV or orally Activated by Cyt P450, eventually •

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Phosphoramide mustard: anti-tumor effect

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has the metabolite called acrolein (Hemorrhagic cystitis) Less GI and platelet effects (due to high concentrations of aldehyde dehydrogenase in these tissues)

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Fulminant cardiac toxicity at very high doses

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Wide range of application: Lymphomas (in CHOP regimen), Leukemias, Breast cancer [adjuvant

and

primary

of

plasma

Carmustine (BCNU): for gliomas, brain therapy in conjunction with BMT

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70% excreted in the urine

15-30%

tumors; multiple myeloma and high dose

generating phosphoramide mustard and •

penetration:

concentration

•

acrolein

CSF

Local

application

operatively

in

of

carmustine

biodegradable

intra-

polymers

(wafers) •

Phenobarbital: increase clearance of BCNU (inducer of liver microsomal enzyme).

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Causes unusually delayed myelosuppression

Carmustine (BCNU): can be applied to brain during surgery Phenobarbital: increase clearance of BCNU (inducer of liver microsomal enyme)

metastatic],

autoimmune diseases)

8. DECARBAZINE used with doxorubicine, bleomycin, vinblastine, decarbazine) for Hodkins Lymphoma can cause fever and malaise which can be counteracted by giving acetominophen before giving carbazine Used in the ABVD regimen for Hodgekin’s •

3. IFOSFAMIDE requires higher dosages than cyclosphamide because it is monofunctional greater extent of hemorrhagic cystitis but  needs mesna to not aggravate bladder  (mesna reacts with acrolein used in sarcomas (soft tissue or osteogenic sarcomas) •

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Lymphoma

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system (since this is an amino acid) •

Used in high dose myeloablative therapy before bone marrow transplantation

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active

metabolite:

MTIC:

triazenoimidazole

carboxamide •

Photosensitive

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Used in malignant melanoma

Now used pricipally for multiple myeloma (in combination with prednisone).

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Generates monomethyl

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Bleomycin,

Vinblastine, Dacarbazine). •

4. MELPHALAN for BONE MARROW TRANSPLANTATION Transported via amino acid-transport

(Doxorubicine,

Isolated limb perfusion treatment (for melanomas and sarcomas

9. TEMOZOLOMIDE  Another drug that passes BBB analog of Decarbazine (oral) used in gliomas, as sole agent or in combination with radiation therapy  Orally administered of Dacarbazine Generates MTIC • • •

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5. CHLORAMBUCIL used for CHRONIC B-CELL LYMPHOCYTIC LEUKEMIA used in immunosuppresive therapy

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ANTIMETABOLITES Specific for S phase •

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Metabolite: similar in structure with another substance but different enough to interfere with normal functions

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Folic Acid Analog

Pyrimidine Analogs

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Needs vitamin B and folic supplementation to limit toxicity

acid

3. 5-FU PYRIMIDINE ANALOGS IV *If you give it bolus (500mg), it can cause myelosuppression; if it is infusional it would be mucositis and GI side effects Inhibits thymidilate synthase enzyme Incorporated directly into DNA and RNA Inactivated by Dihydropyrimidine •

 Methotraxate  Pemetraxed

 5-FU

(prodrug:

Capecitabine)  Cyratabine  Gemcitabine

Purine Analogs

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 Mercaptopurine  Thioguanine  Fludarabine  Cladribine

1. Methotrexate inhibits DHFR (dihidrofolatereductas (dihidrofolatereductase) e) kills cells during S-phase its importance is than it can accumulate in 3RD SPACES: ascites, plural effusion, subcutaneous edema One of two drugs than you can give intrathecally (through spinal needle, inside CSF) can be given oral and IV administration

Dehydrogenase enzyme (DPD) in the liver •

Primary excretion: renal

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Photosensitive

Toxicity •

Bolus: myelosuppression

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Infusional: mucositis, GI side effects

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Note: 

Leucovorin with 5-FU increases the inhibition of thymidilate synthase increase inhibition of TS  5% react differently to 5-FU, leading to severe toxicities [may have a deficiency in DPD]

Toxicity •

mainly bone marrow suppression Intrathecal: meningismus, seizures

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Teratogenesis, dermatitis, pneumonitis

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Clinical use Childhood ALL (acute lymphocytic leukemia) Intrathecal prophylaxis for high grade lymphomas Choriocarcinoma *Get ready to give antidote which is leucovorin (in high doses of methotrexate) High dose methotrexate (with leucovorin rescue) Relapsed non- hodgkin’s lymphomas Osteosarcoma Leukemias Leucovorin given until methotrexate levels -8 falls below 2 x 10 M Alkalinization of urine to facilitate excretion • •

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Clinical uses backbone in adjuvant and metastatic treatment of colorectal and breast cancer *Adjuvant: after surgery, add on treatment. To eliminate any other  microscopic sites that may be circulating in the body  Colorectal: leucovorin, oxaliplatin, irinotecan Breast: together with anthractyclines and alkylating agents; adjuvant and metastatic Also beneficial in head & neck cancers, •

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cervix, bladder, prostate, pancreas and ovary

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Mechanisms of Resistance DHFR mutation, decreased affinity  unable to polyglutamate methotrexate impaired transport into cells icreased DFHR concentration • • • •

2. PREMETREXED Inhibits tumor enzymes and GRFT  multifolate antagonist  • •

Clinical • •

1st line-metastatic mesethlioma 2nd line-metastatic non-small cell lung cancer

4. CAPECITABINE pro-drug of 5-FU [inactivated first] oral administration converted to 5-FU through the ezyme thymidine phosphorylase *TP has a higher concentrations in tumor cells usually take daily for 14 days in a 3 week cycle • • •

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Primary toxicity Hand foot syndrome (palmo-plantarerythrodyesthesia)- a painful, red hands which heals after regimen is completed, or reduce the dosage on successive cycles diarrhea/vomiting •

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5. CYTARABINE Analog of 2-deoxycytidine Converted by deoxycytidine kinase to an active form: 5’ monophosphate nucleotide Incorporated in DNA and inhibits DNA polymerase Deactivated by cytidine deaminase Given IV (GIT has high levels of cytidine deaminase) widely used for childhood cancers ALL (acute lymphocytic leukemia) can be given intrathecally (next to methrotrexate) conjuctivitis [give them steroids]

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resistance

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Deficiency in HGPRT enzymes may lead to

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Used

mostly

to

treat

childhood

cancers,

specifically Acute Lymphocytic Lymphocytic Anemia (ALL)

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A. GUANINE ANALOGS

a. Mercaptopurine

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- used for induction of remission and maintenance for ALL.

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b. Thioguanine

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- also used to treat childhood cancer, ALL.

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B. ADENOSINE ANALOGS

a. Fludarabine

Toxicity Myelosuppression: 3 cell lines: anemia,

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thrombocytopenia and leukopenia

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depletes CD4 T-cells (helper cells)

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GI disturbances, conjunctivitis

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Patient is like infected with HIV, susceptible

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Neurotoxicity/seizures after intrathecal

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used to treat INDOLENT LYMPHOMA

to opportunistic infections like TB.

b. Cladribine

Clinical uses Induction of remission in ALL (high dose: 23g/m2) Non hodgkins’ lymphomas

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depletes CD4 T-cells

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seldom used nowadays

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REMEMBER: used to treat HAIRY CELL

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LEUKEMIA Mechanism of resistance Deficiency in deoxycytidine kinase •

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Increased cytidine deaminase

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Reduced affinity of DNA polymerase

ANTI-MITOTIC AGENTS •

Cell specific agents

A. VINCA ALKALOIDS

6. GEMCITABINE inhibits DNA polymerase, ribonucleotide reductase incorporates into DNA causing strand termination also activated by deoxycytidine kinase given IV For a long time only successful drug against pancreatic cancer given from 30 minutes to one hour. any longer than that you'll have severe hematologic conditions A relatively mild chemotherapy drug: no vomiting or hair loss [ checked via CBC for mild supression]

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from periwinkle plant

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M-phase specific

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Binds

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tubulin

causing

dissolution

of 

MICROTUBULES

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Therefore,

cell

division

will

arrest

at

METAPHASE

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to

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RESISTANCE:

Increased

P-glycoprotein

expression (drug efflux pump); reversed by Ca channelblockers (Verapamil)

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This drug is VESICANT, can burn not only the vein, but the entire hand.

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a. Vincristine •

LYMPHOMA:

Cyclophospamide,

Toxicity •

NON-HODGKIN’S

myelosuppression (related with duration of  infusion)

Prednisone,

Doxorubicin (CHOP) •

HODGKIN’S

LYMPHOMA:

Mechlorethamine, Clinical use First line in metastatic pancreatic cancer •

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Also in breast, cervix and ovarian cancer

with

Prednisone,

Procarbazine (MOPP) •

First line in metastatic NSCLCA (with platinum)

with

TOX: Neurotoxicity , can affect nerve supply of GIT causing severe constipation

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Maximum single dose: 2mg (regardless of  size of patient)

PURINE ANALOGS •

Good substrates for HGPRT converting them to ribonucleotides

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b. Vinblastine

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LYMPHOMA :

HODGKIN’S

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Doxorubicin,

Dacarbazine,

with Bleomycin

TOPOISOMERASE-INTERACTIVE AGENTS

(ABVD) TESTICULAR TUMORS : with Bleomycin and

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TOX: Myelosuppression

c.

Responsible for uncoiling or untangling DNA

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Reduces chromosomal torsion in super coiled

Topoisomerase I: A. CAMPTOTHECINS-

Vinorelbine CA

GLUCORONIDATION by UGT1A1

from bark of yew tree

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Acts on metaphase

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Promote rather than inhibit microtubule

Should not begiven to patients with

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Criggler Najar, Gilbert’s syndrome or

severe hepatic disease (high risk of severe

formation However,

it

prevents

separation

toxicity)

of 

chromatids (so wala din!)

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Converted to active metabolite: SN-38

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METASTATIC COLORECTAL CANCERS: with 5-FU, Leucovorin, or Capecitabine

a. Paclitaxel •

high incidence of allergic reactions

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Has anaphylactic phases because of 

cervical, ovarian, gastric cancer ~DIARRHEA  Acute Phase-cholinergic mediated

after infusion PRE MEDS: steroids and anti- histamine

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BREAST CANCER: Adjuvant, metastatic, in

TOX: ~NEUTROPENIA

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Patient should not be left alone 15-20

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Also used to treat: SCLCA, NSCLCA,

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CREMOPHOR vehicle

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PRE MEDS : atropine

 Delayed Phase- probably SN-38

mediated

different combinations with Doxorubicin •

and/or cyclophosphamide •

LUNG CANCER: with platinum agents

- used to treat METASTATIC OVARIAN

disease

•

CANCER

OVARIAN CANCER: withplatinum agents for adjuvant or metastaticdisease TOX: ~GLOVE-STOCKING sensory

Topoisomerase II: A. EPIPODOPHYLLOTOXINS

neuropathy (numbness of hands and feet)

- from mandrake plant (rememberthis plant

~Neutropenia

from Harry Potter??) •

b. Docetaxel •

Less allergic reactions

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more potent than Paclitaxel

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Usual substitute for Paclitaxel

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TOX: more pronounced Neutropenia

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METASTATIC NSCLCA: singly or with

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used to treat Testicular cancers, cancers , SCLCA, NSCLCA with Cisplatin

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Patients with LOW ALBUMIN are in risk of  having INCREASED TOXICITY due to INCREASED FREE FRACTION

BREAST CANCER :Adjuvant, neoadjuvant •

and metastatic •

Stabilizes Topo-II cleavable complexes

a. Etoposide

platinum agents •

Long term complication is SECONDARY MALIGNANCY

HEAD AND NECK CANCERS: with platinum

b.

and 5-flurouracil

Teniposide - used to treat GLIOBLASTOMA •

c. EPOTHILONES •

Similar MOA withTaxanes

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Treatment for highly resistant Breast CA

addressed by loperamide

b. Camptothecins-Topotecan

cisplatin or carboplatin for metastatic •

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Major excretion pathway:

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Topoisomerase

a. Camptothecins- Irinotecan

B. TAXANES

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stabilize

cleavable complex

adjuvant in metastatic NSCLCA and breast

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DNA that may interfere with cellular function.

Cisplatin •

Not cross resistant

c.

Can cross Blood- Brain- Barrier

ANTI- TUMOR ANTIBIOTIC

i. Anthracyclines

6

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Tumor antibiotic from Streptococcus

-

species

Most dangerous: HUS (hemolytic uremic syndrome) - rare

Doxorubicin •

representative drug

Platinum compounds:

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Binds with Topo-II*

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Generate free radicals*

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Intercalates DNA*

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Promotes Apoptosis*

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Any changes in * will result to resistance

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TOX: Dose-limiting: CARDIOTOXICITY (due to

Forms DNA ‘adducts’ (forms distortions to the contour of the DNA), which are recognized by MMR (mismatch repair enzymes) and later leads to cell death Forms intrastrand and interstrand cross-links. Enters cells by diffusion Resistance: Defects or deficiencies in MMR Increased activity of NER (nucleotide excision repair). Not affected by P-glycoprotein 1. Cisplatin: - A.k.a cis-diamminedichloropl cis-diamminedichloroplatinum atinum (CDDP) - Given intravenously in normal saline solution - Initial half life of 25-50 minutes, then terminal of 24 hours - Photosensitive - Clinical uses: Germ cell tumors, Lung cancer, head and neck cancers, ovarian cancer. Curative even in advanced germ cell tumors •

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generation of free radicals) 2

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Give only cumulative dose of 450mg/m of  450mg/m

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Used to treat lymphomas, leukemias, breast cancer, sarcomas, SCLCA

Liposomal Doxorubicin •

Less cardiotoxic, less neutropenia,

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used in ovarian cancer, lymphomas

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TUMOR ANTIBIOTICS

1. Anthracyclines (look up!) 2. Bleomycin: - Causes oxidative damage to DNA producing single and double strand breaks. - Administered IV, IM, intravesical. - Renal exrection: t1/2 3hours - Clinical uses: germ cell tumors, HL and NHL. - Toxicities: Pulmonary fibrosis ( important indicator! cummulative dose >250U); supportive treatment Initial sign is decline in CO2 diffusion capacity (measured using DLCO and pulmonary function testing) - Little myelosuppression - Cutaneous toxicity: hyperpigmentation, keratosis •

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Trivia : if not for cisplatin Lance Armstrong would have been dead long ago due to his testicular cancer which spread to the brain! :D

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3. Mitomycin: - Common indication: anal cancer - Given alone or combination with radiation theraphy - From Streptococcus caespitosus - Becomes an alkylating agent after intracellular enzymatic alterations - Cross links at N6 of adenine and O6,N7 of guanine. - IV administration - Elimination by chemical conjugation, and less than 10% excreted in urine and bile - Clinical uses: Radiosensitizer for anal cancer Cervix, stomach, breast, bladder (intravesical), lung, head and neck - Toxicity: myelosuppression • •

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Toxicity: Renal toxicity: tubular damage prevented by hydration and diuresis Myelosuppression Ototoxicity (high frequency hearing loss). Electrolite abnormality : Hypomagnasemia, hypokalemia, hypocalcemia Most emetogenic chemotherapeutic drug •

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2. Carboplatin - Less reactive than cisplatin, better tolerated - Less emetogenic, less nephro/neuro/ototoxicity - More pronounced neutropenia - Half life: 2 hours - Oxaliplatin - Dose computed as: (GFR+25) x AUC (computed based on creatinine clearance)

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Refrain using when there is kidney damage Clinical uses: Ovarian cancer, lung cancer, lymphomas, head and neck cancers, bladder cancer, germ cell tumors Clinical trials demonstrate equivalence with cisplatin in lung and ovarian cancers; inferior in head and neck and germ cell tumors Less neutrophinic , nephrotoxicity, neurotoxic but more neuropathic Produces more bulky adducts Least affected by MMR abnormalities Long terminal half life (273 hours) Clinical uses: GI cancers: Adjuvant and metastatic colorectal cancers; Gastric cancers (also for pancreatic cancer) Ovarian, germ cell, cervical cancer. Toxicity: Dose limiting toxicity: Peripheral Neuropathy Less neutropenia •

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OTHERS…

1.

L-Asparaginase Enzyme from E. coli Deprives cancer cells of essential LAsparagine blocking protein synthesis Component in regimens for ALL Toxicity: Hypersensitivity reactions (foreign protein) Minimal BM and GI toxicity Hyperglycemia, Hypoalbuminemia, protein C and S deficiency (protein C and S are anti t hrombotic)  –  –

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2. Hydroxyurea Used for hematologic malignancies Inhibits enzyme r ibonucleoside diphosphate reductase (converts ribonucleotides to deoxy) Favors incorporation of other drugs (Cyta, Gemcitabine, Fludarabine Excellent oral bioavailability (80100%) 4th drug that crosses BBB Given orally Urinary excretion Clinical uses: Myeloproliferative diseases: polycythemia, CML, thrombocytosis Sickle cell disease  –

Toxicity: Myelosuppression: leukopenia, thrombocytopenia, anemia 3. Mitotane: - Similar to DDT insecticide - Preferential attack of adrenal cortical cells - Orally administered - Clinical use: Adrenocortical carcinoma - Toxicity: Anorexia, nausea Depletion of endogenous corticosteroids HORMONAL AGENTS  –

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1. Steroids (Adrenocorticosteroids) (Adrenocorticosteroids) - Most commonly used: Prednisone Dexamethasone - Able to induce remissions in hematologic cancers and responses in solid tumors - Valuable component in NHL, HL, CLL, ALL - MOA?- promote apoptosis - Side effects: Immunosuppression, glucose intolerance, osteoporosis, water retention, GI ulcers • •

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2. Aromatase Inhibitors - Most commonly used: Letrozole (Femara) Anastrozole (Arimidex) Exemestane (Aromasin) - Inhibits aromatase enzyme that converts androgens to estrogens - Aromatase enzyme are in adrenal glands and adipose tissue. - Indicated for post-menopausal ER (estrogen receptor)/PR( progesterone receptor) + breast cancer patients in adjuvant, neoadjuvant, and metastatic setting. - Side effect: Bone mineral density, bone pains, increased fracture rates. • • •

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3. Anti-Estrogens - Tamoxifen: binds to ER receptors preventing binding to DNA - Eventually decresaes autocrine stimulation of breast cancer cells. - Has an agonist effect on endometrial cells and increases thrombotic risk - Indicated in ER/PR+ pre or postmenopausal breast cancer treatment (adjuvant or metastatic) - Side effect: thrombosis risk, endometrial CA, hot flashes, nausea, vomiting, menstrual irregularities

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Question: Why is Tamoxifen given to pre

 –

Side effects: fever, chills

and post menopausal while Aromatase inhibitors are only given to post

TARGETED THERAPIES

menopausal cancer patients?

Signal transduction:

Answer: Premenopausal patients have

Relaying outside signals towards the

functioning ovaries which produces most of 

nucleus causing specific gene expression and

the estrogen but your aromatase inhibitors

transcriptions of proteins proteins promoting cell growth, growth,

only inhibits estrogen production from your

proliferation, angiogenesis, etc

adrenal glands and adipose tissues so effects of Aromatiase will not work because you still have formidable amounts of  estrogen in the body. Comparing to tamoxifen, it blocks the receptors. So aromatase inhibitors are given to post menopausal patients because their ovaries are already not functioning

4. GnRH analogs: - PROTOTYPES: Goserelin, Leuprolide - Administered intramuscularly or subcutaneously - Initially stimulate FSH and LH production by the pituitary, then later cause negative feedback inhibition. - Estrogen levels fall to post-menopausal values - Androgen levels fall to castrate values. - Used in breast cancer and prostate cancer - Can have initial ‘FLARE’ REACTION which can be controlled by concomitant anti-androgens or anti-estrogens 5. Anti-Androgens - Bicalutamide - Flutamide - Nilutamide - Binds to Androgen receptors and causes complete androgen blockade - Usually given with GnRH analogs - Side effects: decreased libido, hot flashes, gynecomastia, mastodynia, paradoxical stimulation of androgen receptors (minor side effect) - Usually used for patients with prostate cancer

1. Monoclonal antibodies (Mab’s): - Target extracellular receptors or Ligands - Tyrosine Kinase Inhibitors (TKI’s): Targets intracellular receptor - Associated enzyme (tyrosine Kinases) - Favorable side-effect profile - Cytostatic - Usually combined with cytotoxic agents Monoclonal antibodies (Mab’s): -

Target extra cellular receptor or ligands Trastuzumab: Her2 receptor in breast cancer Bevacizumab: Vegf ligand to inhibit angiogenesis Cetuximab: EGFR receptor in colorectal and head and neck cancers Panitumomab: EGFR receptor in colorectal cancers Rituximab: CD20 receptor in B-cell lymphomas Monoclonal antibodies side Effects: •

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Trastuzumab: CHF (especially with anthracyclines) Bevacizumab: Hypertension, bleeding, proteinuria

Cetuximab: skin rashes Common to all: Hypersensitivity reactions (proteins) 2. Tyrosine Kinase Inhibitors: - Targets intracellular receptors - Associated enzymes (tyrosine kinase) - Imatinib (Gleevec): Bcr-Abl TKI in CML; CD117 TKI in GIST • •

BIOLOGIC RESPONSE MODIFIERS

1. Interleukin-2: Not directly cytotoxic Expands a T-cell response that is cytolytic for tumor cells Uses: Melanoma, Renal cell carcinoma, AML Toxicity: hypotension, peripheral edema, azotemia 2. G-CSF: Filgrastim/ Lenograstim: expands population of neutrophil precursors Prophylaxis for chemotherapy induced neutropenia  –  –

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Gefitinib: EGFR TKI in NSCLCA Erlotinib: EGFR TKI in NSCLCA Sunitinib: Multikinase; in Renal cell carcinoma

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Sorafenib: Multikinase: in Renal and Liver cancer

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Lapatinib: EGFR and Her2 TKI in breast and head and neck CA.

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Common side effect: rashes, asthenia, weakness

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PROTEOSOMES INHIBITORS

b. Prevent or slow the subsequent development of drug resistance c. Broader range of interaction between the drugs with different MOA’s and the heterogenous tumor d. Drugs can be combined if: 1. Each drug is effective as a single agent 2. Drugs that cause complete remission are preferred 3. If drugs equally effective, choose the ones with less or nonoverlapping toxicities 4. Drugs should not affect each other’s PK 5. Cytotoxics and biologics

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Waste basket of the cell which eliminates and degrades proteins Clinical Significance: NFKappa-B is a transcription factor/promoter. Once it becomes available available to the nucleus it will induce self proliferation, angiogenesis and cell survival which may lead to cancer. It stays inactive if bound to protein I-KappaB. Once proteosome degrates IKB then NFK-B becames free thus, damaging the cell. The job of proteosomes inhibitors is to keep NFK-B glued glued to IKB inhibiting its mechanism. - Bortezumib - Used for multiple myeloma mTOR INHIBITORS - Mammalian target of rapamycin - Serine/threonine protein kinase involving signal transduction Everolimus - Used in pancreatic and endocrine. - Temsirolimus - renal cancer (PALIMUS!! :D)

e. Combine... 1. Oxaliplatin + Vincristine? No. Both are neuropathic 2. Paclitaxel + Carboplatin? Yes. Both can cause neutropenia but not that severe 3. Mechlorethamine + Dacarbazine? agents so No. Both are alkalating agents they will just compete with each other 4. Etoposide + Cisplatin? Yes. Different side effect profile 5. Paclitaxel + Carboplatin + Bevucizumab? Yes because Bevucizumab have different different side side effect profile from the two. 6. Innotecan + cetuximab? Yes 7. Bevacizumab + Ellotinib . Yes. Bevacizumab targets VGEF while Ellotinib target ECFR

DEFINITION OF TERMS

1. Primary Chemotherapy -drug theraphy administered as the primary treatment with no alternative treatment (NHL, SCLCA, Wilm’s)

2. Adjuvant Chemotheraphy -drug theraphy given after a definitive treatment, whether surgery or radiation therapy (RT)

3. Neoadjuvant Chemotheraphy -drug treatment given before a definitive definitive treatment COMBINATION CHEMOTHERAPY a.

Provides maximal cell kill

Drugs that can cause Blood-Brain-Barrier a.

Methotrexate (only in high doses)

b. Carmustine c.

Temozolomide

d. Treniposide e. Hydroxyurea

-END OF TRANSCRIPTION“Then you call on me and come to pray to me, and I will hear you. You will seek me and find find me. When you seek, seek Me with all your heart.” Jeremiah 29:12

Disclaimer: This tranx is based mostly on recording of Doc Dexter’s lecture! Please read your very expensive  books for more information!  information! 

Greetings: Hello to all IDK! You know who you are!!! Hello to our VERY EXPENSIVE friends!!! Hello to UST- Sampaloc Chapter!!! Hello to Ailyn O. Villamer Sa mga balak mag-top (see above), babaan nyo ang MPL please?! BTW, nasaan na ang “Wow Mangga!!”?

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