2011 07 Pharmacology Chemotherapy for Cancer

8/6/2019 2011 07 Pharmacology Chemotherapy for Cancer

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OutlineI. Cytotoxic agent

a. Alkylating agentsb. Anti-metabolitesc. Platinumsd. Tumor antibioticse. Anti-mitotic agents

II. Hormonal Treatmenta. Anti-Estrogensb. GnRH agonists

c. Androgen receptor blockersIII. Biologic Response Modifiers

a. Interleukinb. G-CSF

IV. Targeted Agentsa. Monoclonal antibodiesb. Tyrosine kinase inhibitors

CANCER• A disease characterized by an abnormal and

uncontrolled proliferation of cells which can

metastasize or spread (the difference fromneoplasia, the aspect of metastasis)• Triggered by an interplay of genetic and

environmental factors

Logarithmic Growth of Cancer Cells

• 10 9 (a billion cancer) will produce a 1 cmtumor

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• 10 12 cancer cells will result in death of the

host or patient

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

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

Why do solid tumors have longer double time thanhematologic cancers?

Solid tumors have a basement membraneand 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 tumorburden is low, but growth rate is high.Once it plateaus on the logarithmic scale, then it isvery difficult to treat*You'd like to catch the cancer in the 10^9 stage,this is when they are more treatable. The growthrate is the factor which makes it treatable or not.

Primary chemotherapy : drug therapy

administered as the primary treatment with noalternative treatment (NHL, SCLCA, Wilm’s) Adjuvant chemotherapy : drug therapy givenafter a definitive treatment, (whether surgery or RT)Neoadjuvant chemotherapy: drug treatment given before a definitive treatment

They found out during the first world war thatmustard gas is an irritant to skin, eyes andrespiratory tract. Induced leukopenia, bonemarrow, aslasia, and dissolution of lymphoid tissue.The mother of all chemotherapy is CYTOTOXIC.Difficulty in giving chemotherapy drugs is thatthere is an effective dose (the minimum dosing that

you can have a beneficial effect of the host) whilethe toxic dose, where if you go to the upper limit.

Cytotoxic drugs therapeutic window is very narrowcompared to other drugs. A lot of cytotoxic drugswould entail giving a toxic dose for meaningfulresponse to be achieved.Another rationale is that normal cells would recover

more faster than the cancer cells. Thats why wepermit the toxicity in order to eradicate the cancercell in hopes the normal cell recovers.Chemotherapy comes in cycles (rest for three weeksand give another cycle). Leukopenia is a side effectof therapy. Once the bone marrow is fullyrecovered you can start again with another cycle.That is the rationale behind cycling of chemotherapy.

Subject: PharmacologyTopic: Chemotherapy/ Anti-Neoplastic

AgentsLecturer: Dr. Paul Dexter SantosDate of Lecture: July 20, 2011Transcriptionist: Teriyaki, Sushi andBrewed CoffeePages: 10

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Cancer treatment agentsCYTOTOXIC AGENTS [kill everything]

1. Alkylating AgentNitrogen mustard

2. AntimetabolitesFolic acid analogs: methotrexatePyrimidine analogs: 5-FU

Purine analogs:Mercaptopurine3. Anti-Mitotic Agents

Vinca alkaloids and taxanes

Phase Non-specific* Phase Specific

o Alkylating Agentso Platinum

Compoundso Tumor

Antibiotics

o Cytarabineo Hydroxyurea

(Synthesis)o Methotrexateo 6-Mercapo Vinca's And

Taxanes (Mitosis)*Can kill any part of the cell cycle

ALKYLATING AGENTS• TARGETS DNA• Reacts with or ‘alkylates’ electron bridge

atoms in the cells (electrophilecharacteristics)

• FORMS COVALENT BONDS WITH DNACOMPONENETS (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 AREDETECTED BY THE REPAIR SYSTEM THAT

CAN LEAD TO CELL CYCLE ARREST ORAPOPTOSIS (REQUIRES A P53 SYSTEM,GUARDIAN OF THE CELL)

Mechanism Of Resistance• Inactivation by other electron-rich

molecules within the cell: Glutathione• Repair of DNA damage that the agents

produce: enzyme O6-alkylguanine-

alkyltransferase (for nitrosoureas)• Increased aldehyde dehydrogenase enzyme

(inactivates cyclophosphamide)• Bcl-2 over expression (anti-apoptotic gene)

*If you're undergoing chemotherapy with analkylating 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 bodyRBCs, WBCs, Platelets, Bone marrow, Hair(that's why some chemotherapy drugs caninduce a hair loss-alopecia)

• Gastrointestinal toxicity: nausea andvomiting less than the platinums (that's whyyou vomit, have abdominal pain, diarrhea)

• Gonadal toxicity: germ cell depletionwithout damaging sertoli cells.Oligospermia, aspermia, amenorrhea

• sperm cells are shielded by blood-testesbarrier, but some can pass through thebarrier. But not enough to induce completesterility

• Pulmonary toxicity: busulfan, pneumonialike symptoms

• Teratogenicity (15% risk of malformation if given in the first trimester) Carcinogenesis:in the long term you may have an increasedrisk of developing a secondary cancer

• Carcinogenesis: acute leukemia in about

5%. More common in melphalan vscyclophosphamide

• Immunosuppression

1. MECHLORETHAMINE (aka Mustargren)• First original nitrogen mustard• causes a bifunctional alkylation• given IV

*Always make sure the IV line is flowingwell. you can run the risk of extravasation(meaning the drug is going outside blood

vessel into subcutaneous tissue). Thenecrosis will be severe and requires plasticsurgery 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



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Severe necrosis from extravasation

2. CYCLOPHOSPHAMIDE• Presently, most widely used alkylating

agent • Bifunctional alkylates • Can be given IV or orally• Activated by Cyt P450, eventually

generating phosphoramide mustard andacrolein

• 70% excreted in the urine• Phosphoramide mustard: anti-tumor effect• has the metabolite called acrolein

(Hemorrhagic cystitis)• Less GI and platelet effects (due to high

concentrations of aldehyde dehydrogenasein these tissues)

• Fulminant cardiac toxicity at very high doses• Wide range of application: Lymphomas (in

CHOP regimen), Leukemias, Breast cancer[adjuvant and primary metastatic],autoimmune diseases)

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)

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

system (since this is an amino acid)• Now used pricipally for multiple myeloma

(in combination with prednisone).• Used in high dose myeloablative therapy

before bone marrow transplantation• Isolated limb perfusion treatment (for

melanomas and sarcomas

5. CHLORAMBUCIL• used for CHRONIC B-CELL LYMPHOCYTIC

LEUKEMIA• used in immunosuppresive therapy

autoimmune disease• orally administered

6. BUSULFAN• Characteristic toxicity: VENOCCLUSIVE

DISEASE OF THE LIVER (VOD) AT HIGHDOSES

• cross-links DNA •

both oral and IV administration • presently used in high-dose therapy in

conjunction with BMT: 16mg/kg (for CML)

7. NITROSOUREAS• Think of CNS• Cross BBB• Alkylation at O6 guanine• CSF penetration: 15-30% of plasma

concentration• Carmustine (BCNU): for gliomas, brain

tumors; multiple myeloma and high dosetherapy in conjunction with BMT

• Local application of carmustine intra-operatively in biodegradable polymers(wafers)

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

• Causes unusually delayed myelosuppression

Carmustine (BCNU): can be applied to brain duringsurgeryPhenobarbital : increase clearance of BCNU (inducerof liver microsomal enyme)

8. DECARBAZINE• used with doxorubicine, bleomycin,

vinblastine, decarbazine) for HodkinsLymphoma

• can cause fever and malaise which can becounteracted by giving acetominophenbefore giving carbazine

• Used in the ABVD regimen for Hodgekin’sLymphoma (Doxorubicine, Bleomycin,Vinblastine, Dacarbazine).

• Generates active metabolite: MTIC:monomethyl triazenoimidazolecarboxamide

• Photosensitive• Used in malignant melanoma

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

ANTIMETABOLITES• Specific for S phase



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• Metabolite: similar in structure withanother substance but different enough tointerfere with normal functions

Folic Acid Analog Pyrimidine Analogs

Methotraxate Pemetraxed

5-FU (prodrug:Capecitabine)

Cyratabine Gemcitabine

1. Methotrexate• inhibits DHFR (dihidrofolatereductase)• 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 giveintrathecally (through spinal needle, insideCSF)

• can be given oral and IV administration

Toxicity• mainly bone marrow suppression• Intrathecal: meningismus, seizures• Teratogenesis, dermatitis, pneumonitis

Clinical use• Childhood ALL (acute lymphocytic leukemia)• Intrathecal prophylaxis for high grade

lymphomas• Choriocarcinoma

*Get ready to give antidote which isleucovorin (in high doses of methotrexate)

• High dose methotrexate (with leucovorinrescue)

• Relapsed non- hodgkin’s lymphomas

• Osteosarcoma• Leukemias• Leucovorin given until methotrexate levels

falls below 2 x 10 -8 M• Alkalinization of urine to facilitate excretion

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

• Needs vitamin B and folic acidsupplementation to limit toxicity

3. 5-FUPYRIMIDINE ANALOGS

• IV*If you give it bolus (500mg), it can causemyelosuppression; 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

Dehydrogenase enzyme (DPD) in the liver• Primary excretion: renal• Photosensitive

Toxicity• Bolus: myelosuppression• Infusional: mucositis, GI side effects

Note: Leucovorin with 5-FU increases the

inhibition of thymidilate synthase increaseinhibition of TS

5% react differently to 5-FU, leading tosevere toxicities [may have a deficiency inDPD]

Clinical uses• backbone in adjuvant and metastatic

treatment of colorectal and breast cancer*Adjuvant: after surgery, add ontreatment. To eliminate any other microscopic sites that may becirculating in the body

• Colorectal: leucovorin, oxaliplatin,irinotecan

• Breast: together with anthractyclines andalkylating agents; adjuvant and metastatic

• Also beneficial in head & neck cancers,cervix, bladder, prostate, pancreas and

ovary

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 tumorcells

• usually take daily for 14 days in a 3 weekcycle

Primary toxicity• Hand foot syndrome (palmo-plantar-

erythrodyesthesia)- a painful, red handswhich heals after regimen is completed, orreduce the dosage on successive cycles

• diarrhea/vomiting

Purine Analogs

Mercaptopurine Thioguanine Fludarabine Cladribine



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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]

Toxicity• Myelosuppression: 3 cell lines: anemia,

thrombocytopenia and leukopenia• GI disturbances, conjunctivitis•

Neurotoxicity/seizures after intrathecal

Clinical uses• Induction of remission in ALL (high dose: 2-

3g/m2)• Non hodgkins’ lymphomas

Mechanism of resistance• Deficiency in deoxycytidine kinase• Increased cytidine deaminase• Reduced affinity of DNA polymerase

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 severehematologic conditions

• A relatively mild chemotherapy drug: novomiting or hair loss [ checked via CBC formild supression]

Toxicity• myelosuppression (related with duration of

infusion)

Clinical use• First line in metastatic pancreatic cancer• First line in metastatic NSCLCA (with

platinum)• Also in breast, cervix and ovarian cancer

PURINE ANALOGS• Good substrates for HGPRT converting them to

ribonucleotides

• Deficiency in HGPRT enzymes may lead toresistance

• Used mostly to treat childhood cancers,specifically Acute Lymphocytic Anemia (ALL)

A. GUANINE ANALOGSa. Mercaptopurine

- used for induction of remission andmaintenance for ALL.

b. Thioguanine- also used to treat childhood cancer, ALL.

B. ADENOSINE ANALOGSa. Fludarabine

• used to treat INDOLENT LYMPHOMA • depletes CD4 T-cells (helper cells) • Patient is like infected with HIV, susceptible

to opportunistic infections like TB. b. Cladribine

• depletes CD4 T-cells • seldom used nowadays • REMEMBER: used to treat HAIRY CELL

LEUKEMIA

ANTI-MITOTIC AGENTS• Cell specific agents

A. VINCA ALKALOIDS• from periwinkle plant• M-phase specific• Binds to tubulin causing dissolution of

MICROTUBULES• Therefore, cell division will arrest at

METAPHASE• RESISTANCE: Increased P-glycoprotein

expression (drug efflux pump); reversed by Cachannelblockers (Verapamil)

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

a. Vincristine• NON-HODGKIN’S LYMPHOMA: with

Cyclophospamide, Prednisone,Doxorubicin (CHOP)

• HODGKIN’S LYMPHOMA: withMechlorethamine, Prednisone,Procarbazine (MOPP)

• TOX:Neurotoxicity , can affect nerve supplyof GIT causing severe constipation

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



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b. Vinblastine• HODGKIN’S LYMPHOMA: with

Doxorubicin, Dacarbazine, Bleomycin(ABVD)

• TESTICULAR TUMORS : with Bleomycin andCisplatin

• TOX: Myelosuppression

c. Vinorelbine• adjuvant in metastatic NSCLCA and breast

CA

B. TAXANES• from bark of yew tree• Acts on metaphase• Promote rather than inhibit microtubule

formation• However, it prevents separation of

chromatids (so wala din!)

a. Paclitaxel• high incidence of allergic reactions • Has anaphylactic phases because of

CREMOPHOR vehicle • Patient should not be left alone 15-20

after infusion • PRE MEDS: steroids and anti- histamine • BREAST CANCER: Adjuvant, metastatic, in

different combinations with Doxorubicinand/or cyclophosphamide

• LUNG CANCER: with platinum agentscisplatin or carboplatin for metastaticdisease

• OVARIAN CANCER: withplatinum agentsfor adjuvant or metastaticdisease

• TOX: ~GLOVE-STOCKING sensoryneuropathy (numbness of hands and feet)

~Neutropenia

b. Docetaxel• Less allergic reactions • more potent than Paclitaxel • Usual substitute for Paclitaxel • TOX: more pronounced Neutropenia • METASTATIC NSCLCA: singly or with

platinum agents• BREAST CANCER :Adjuvant, neoadjuvant

and metastatic• HEAD AND NECK CANCERS: with platinum

and 5-flurouracil

c. EPOTHILONES• Similar MOA withTaxanes• Treatment for highly resistant Breast CA

• Not cross resistant

TOPOISOMERASE-INTERACTIVE AGENTS• Responsible for uncoiling or untangling DNA• Reduces chromosomal torsion in super coiled

DNA that may interfere with cellular function.

Topoisomerase I:A. CAMPTOTHECINS- stabilize Topoisomerase I

cleavable complex

a. Camptothecins- Irinotecan• Major excretion pathway:

GLUCORONIDATION by UGT1A1 • Should not begiven to patients with

Criggler Najar, Gilbert’s syndrome orsevere hepatic disease (high risk of severetoxicity)

• Converted to active metabolite: SN-38• METASTATIC COLORECTAL CANCERS: with

5-FU, Leucovorin, or Capecitabine• Also used to treat: SCLCA, NSCLCA,

cervical, ovarian, gastric cancer• TOX: ~NEUTROPENIA

~DIARRHEA Acute Phase-cholinergic mediated

• PRE MEDS : atropine Delayed Phase- probably SN-38

mediated• addressed by loperamide

b. Camptothecins-Topotecan- used to treat METASTATIC OVARIANCANCER

Topoisomerase II:A. EPIPODOPHYLLOTOXINS

- from mandrake plant (rememberthis plantfrom Harry Potter??)• Stabilizes Topo-II cleavable complexes

a. Etoposide• used to treat Testicular cancers , SCLCA,

NSCLCA with Cisplatin • Patients with LOW ALBUMIN are in risk of

having INCREASED TOXICITY due toINCREASED FREE FRACTION

• Long term complication is SECONDARYMALIGNANCY

b. Teniposide- used to treat GLIOBLASTOMA • Can cross Blood- Brain- Barrier

c. ANTI- TUMOR ANTIBIOTICi. Anthracyclines



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• Tumor antibiotic from Streptococcusspecies

Doxorubicin• representative drug• Binds with Topo-II*• Generate free radicals*• Intercalates DNA*•

Promotes Apoptosis*• Any changes in * will result to resistance• TOX: Dose-limiting: CARDIOTOXICITY (due to

generation of free radicals)• Give only cumulative dose of 450mg/m 2

• Used to treat lymphomas, leukemias, breastcancer, sarcomas, SCLCA

Liposomal Doxorubicin• Less cardiotoxic, less neutropenia,• used in ovarian cancer, lymphomas

TUMOR ANTIBIOTICS

1. Anthracyclines (look up!) 2. Bleomycin:

- Causes oxidative damage to DNAproducing single and double strandbreaks.

- Administered IV, IM, intravesical.- Renal exrection: t1/2 3hours- Clinical uses:

• germ cell tumors, HL and NHL.- Toxicities:

• Pulmonary fibrosis ( importantindicator! cummulative dose>250U); supportive treatment

• Initial sign is decline in CO2diffusion capacity (measuredusing DLCO and pulmonaryfunction testing)

- Little myelosuppression- Cutaneous toxicity: hyperpigmentation,

keratosis

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 andbile

- Clinical uses:• Radiosensitizer for anal cancer• Cervix, stomach, breast,

bladder (intravesical), lung,head and neck

- Toxicity: myelosuppression

- Most dangerous: HUS (hemolyticuremic syndrome) - rare

Platinum compounds:• Forms DNA ‘adducts’ (forms distortions

to the contour of the DNA), which arerecognized by MMR (mismatch repairenzymes) and later leads to cell death

• Forms intrastrand and interstrandcross-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-diamminedichloroplatinum

(CDDP)

-

Given intravenously in normal salinesolution- Initial half life of 25-50 minutes, then

terminal of 24 hours- Photosensitive- Clinical uses:

• Germ cell tumors, Lung cancer,head and neck cancers, ovariancancer.

• Curative even in advanced germcell tumors

Trivia : if not for cisplatin Lance Armstrongwould have been dead long ago due to histesticular cancer which spread to thebrain! :D

- Toxicity:• Renal toxicity: tubular damage

prevented by hydration anddiuresis

• Myelosuppression•

Ototoxicity (high frequencyhearing loss).

• Electrolite abnormality :Hypomagnasemia,hypokalemia, hypocalcemia

• Most emetogenicchemotherapeutic drug

2. Carboplatin- Less reactive than cisplatin, better

tolerated

-

Less emetogenic, lessnephro/neuro/ototoxicity- More pronounced neutropenia- Half life: 2 hours- Oxaliplatin- Dose computed as: (GFR+25) x AUC

(computed based on creatinineclearance)



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- Refrain using when there is kidneydamage

- Clinical uses:• Ovarian cancer, lung cancer,

lymphomas, head and neckcancers, bladder cancer, germcell tumors

• Clinical trials demonstrate

equivalence with cisplatin inlung and ovarian cancers;inferior in head and neck andgerm 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 andmetastatic colorectal cancers;Gastric cancers (also forpancreatic cancer)

• Ovarian, germ cell, cervicalcancer.

- Toxicity:• Dose limiting toxicity:

Peripheral Neuropathy• Less neutropenia

OTHERS…

1. L-Asparaginase – Enzyme from E. coli – Deprives cancer cells of essential L-

Asparagine blocking proteinsynthesis

– Component in regimens for ALL – Toxicity:

• Hypersensitivity reactions(foreign protein)

• Minimal BM and GI toxicity• Hyperglycemia,

Hypoalbuminemia, proteinC and S deficiency (proteinC and S are anti thrombotic)

2. Hydroxyurea – Used for hematologic malignancies – Inhibits enzyme ribonucleoside

diphosphate reductase (convertsribonucleotides to deoxy)

– Favors incorporation of other drugs(Cyta, Gemcitabine, Fludarabine

– Excellent oral bioavailability (80-100%)

– 4th drug that crosses BBB – Given orally – Urinary excretion – Clinical uses:

• Myeloproliferativediseases: 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

corticosteroidsHORMONAL AGENTS

1. Steroids (Adrenocorticosteroids)- Most commonly used:

• Prednisone• Dexamethasone

- Able to induce remissions inhematologic cancers and responses insolid tumors

- Valuable component in NHL, HL, CLL,ALL

- MOA?- promote apoptosis- Side effects:

• Immunosuppression, glucoseintolerance, osteoporosis,water retention, GI ulcers

2. Aromatase Inhibitors- Most commonly used:

• Letrozole (Femara)• Anastrozole (Arimidex)• Exemestane (Aromasin)

- Inhibits aromatase enzyme thatconverts androgens to estrogens

- Aromatase enzyme are in adrenalglands and adipose tissue.

- Indicated for post-menopausal ER(estrogen receptor)/PR( progesterone

receptor) + breast cancer patients inadjuvant, neoadjuvant, and metastaticsetting.

- Side effect: Bone mineral density, bonepains, increased fracture rates.

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 endometrialcells and increases thrombotic risk- Indicated in ER/PR+ pre or post-

menopausal 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 preand post menopausal while Aromataseinhibitors are only given to postmenopausal cancer patients?Answer: Premenopausal patients havefunctioning ovaries which produces most of the estrogen but your aromatase inhibitors

only inhibits estrogen production from youradrenal glands and adipose tissues soeffects of Aromatiase will not work becauseyou still have formidable amounts of estrogen in the body. Comparing totamoxifen, it blocks the receptors. Soaromatase inhibitors are given to postmenopausal patients because their ovariesare already not functioning

4. GnRH analogs:

- PROTOTYPES: Goserelin, Leuprolide- Administered intramuscularly or

subcutaneously- Initially stimulate FSH and LH

production by the pituitary, then latercause negative feedback inhibition.

- Estrogen levels fall to post-menopausalvalues

- Androgen levels fall to castrate values.- Used in breast cancer and prostate

cancer- Can have initial ‘FLARE’ REACTION

which can be controlled by concomitantanti-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 androgenreceptors (minor side effect)

- Usually used for patients with prostatecancer

BIOLOGIC RESPONSE MODIFIERS1. 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, azotemia2. G-CSF:

– Filgrastim/ Lenograstim: expandspopulation of neutrophil precursors

– Prophylaxis for chemotherapyinduced neutropenia

– Side effects: fever, chills

TARGETED THERAPIESSignal transduction:

Relaying outside signals towards thenucleus causing specific gene expression andtranscriptions of proteins promoting cell growth,proliferation, angiogenesis, etc

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 neckcancers

- Panitumomab: EGFR receptor• in colorectal cancers

- Rituximab: CD20 receptor in• B-cell lymphomas

- Monoclonal antibodies sideEffects:

• Trastuzumab: CHF (especiallywith 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

- Gefitinib: EGFR TKI in NSCLCA- Erlotinib: EGFR TKI in NSCLCA- Sunitinib: Multikinase; in Renal

cell carcinoma

- Sorafenib: Multikinase: in Renaland Liver cancer

- Lapatinib: EGFR and Her2 TKI inbreast and head and neck CA.

- Common side effect: rashes,asthenia, weakness



PROTEOSOMES INHIBITORS- Waste basket of the cell which

eliminates and degrades proteinsClinical Significance :

NFKappa-B is a transcriptionfactor/promoter. Once it becomes available to thenucleus it will induce self proliferation, angiogenesisand cell survival which may lead to cancer. It stays

inactive if bound to protein I-KappaB. Onceproteosome degrates IKB then NFK-B becames freethus, damaging the cell. The job of proteosomesinhibitors is to keep NFK-B glued to IKB inhibiting itsmechanism.

- 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)

DEFINITION OF TERMS

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

2. Adjuvant Chemotheraphy-drug theraphy given after a definitivetreatment, whether surgery or radiationtherapy (RT)

3. Neoadjuvant Chemotheraphy-drug treatment given before a definitivetreatment

COMBINATION CHEMOTHERAPYa. Provides maximal cell kill

b. Prevent or slow the subsequentdevelopment of drug resistance

c. Broader range of interaction between thedrugs with different MOA’s and theheterogenous tumor

d. Drugs can be combined if:1. Each drug is effective as a single

agent

2. Drugs that cause completeremission are preferred

3. If drugs equally effective, choosethe ones with less or non-overlapping toxicities

4. Drugs should not affect eachother’s PK

5. Cytotoxics and biologics

e. Combine...1. Oxaliplatin + Vincristine? No . Both

are neuropathic2. Paclitaxel + Carboplatin? Yes . Both

can cause neutropenia but not thatsevere

3. Mechlorethamine + Dacarbazine?No . Both are alkalating agents sothey will just compete with eachother

4. Etoposide + Cisplatin? Yes . Differentside effect profile

5. Paclitaxel + Carboplatin +Bevucizumab? Yes because

Bevucizumab have different sideeffect profile from the two.

6. Innotecan + cetuximab? Yes 7. Bevacizumab + Ellotinib . Yes .

Bevacizumab targets VGEF whileEllotinib target ECFR

Drugs that can cause Blood-Brain-Barriera. Methotrexate (only in high doses)b. Carmustinec. Temozolomide

d. Treniposidee. 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 fin d 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!

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. VillamerSa mga balak mag-top (see above), babaan nyo ang MPL please?!BTW, nasaan na ang “Wow Mangga!!”?

2011 07 Pharmacology Chemotherapy for Cancer

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Transcript of 2011 07 Pharmacology Chemotherapy for Cancer