Cancer Chemotherapy

CANCER CHEMOTHERAPY Principles of Cancer Chemotherapy Goal of treatment A. Cure – eradication of every neoplastic cell B. Palliation – alleviation of symptoms and avoidance of life threatening toxicity

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Tumor susceptibility and the growth cycle 4 Phases of the Cell Cycle 1. M phase – period of mitosis (cell division) 2. G1 phase – interval during which RNA, protein synthesis and cellular growth occurs 3. S phase – DNA synthesis 4. G2 phase – synthesis of cellular components required for mitosis 5. Go- resting state where cell is not dividing

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MECH = converted to 6 –thioguanine 5 Phosphate (6-thioGMP) which replace guanine nucleotide and inhibit DNA synthesis Fluorouracil (5 FU) Inhibits thymidylate synthetase thus interferes DNA production Floxuridine (FUDR or 5 FUDR)

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Cell – cycle specific drugs – drugs that inhibit cell replication during a phase of a cycle. Example: Methotrexate – inhibits DNA synthesis during Sphase(Antimetabolite) Others: Bleomycin, Antibiotics, Vinca Alkaloids - They are effective for Cancer with a high growth fraction (e.g – hematologic cancers)

6 – Mercaptopurine the thiol analog of the purine hypoxanthine. It is converted to the corresponding nucleotide – 6-thioinosinic acid 6 TIMP which inhibits the formation of adenine and guanine from Inosinic monophosphate (IMP). Fate: 6 MP is converted to thiouric acid in the liver (this reaction is catalyzed by xanthine oxidase)

6- Thioguanine (6 TG)

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2 Types of Cancer Chemotherapeutic Agents base on its effect on cell cycle

Trimetrexate antimalarial agent, also a potent inhibitor of DNHFR

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MECH= 5 FU is a pyrimidine analog. Interferes the conversion of deoxyuridylic acid to thymidylic acid. 5 FU must be converted to 5 FdUMP-( 5 Fluorodeoxyuridine monphosphate,) which competes with deoxyuridine monophosphate for the enzyme thymidylate synthetase. 5 FU is metabolized in the liver to CO2 which is then expired.

Cell-cycle non specific – agents that are active while the cancer cells are dividing but whose action spans more than one phase of the cycle as well as within Go. • Example: Mechlorethamine, cisplatin, nitrosourceas • they are effective for both high growth fraction as well as low fraction malignancies e.g solid tumors

ANTI CANCER DRUG CLASSIFICATION: I. ANTIMETHABOLITES – are structural analogs of naturally occurring substances – inhibits DNA synthesis. They are S-phase specific (except 5FU) They act in 2 ways: a. By incorporation into a metabolite pathway and formation of a false metabolite b. By inhibition of the catalytic function of an enzyme or enzyme system Antimetabolite a) Folate antagonist : Methotrexate, Trimetrexate b) Purine derivatives : Mercaptopurine ,Thioguanine c) Pyrimidine derivative : Fluorouracil (5 FU), Floxuridine, Cytarabine 1.

Methotrexate Mechanism of Action – competes with folic acid for the active binding sites on dihydrofolate reductase (DHFR) enzyme

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CYTARABINE ( CYTOSINE ARABINOSIDE, ARA –C) Analog of 2 –deoxycytidine • S- CYCLE SPECIFIC • MECHANISM OF ACTION –an pyrimidine antimetabolite ,phoshorylated to the active cytotoxic nucleotide cytosine arbinase triphosphate, an inhibitor of DNA polymerase

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Given parenterally ,not orally because it is deaminated to a noncytotocic product in the intestinal mucosa uses – is an imporatnt component for the treatment of acute leukemias Toxicities – GIT irritation , myelosuppresion , neurotoxicity (cerebellar dysfunction and peripheral neuritis)

II. ALKYLATING AGENTS –are cycle phase nonspecific

• Pharmacokinetic: converted to polyglutamated metabolite which also inhibits DHFR also converted to a 7-OH derivative by hydroxylation – less water soluble – may lead to crystalluria in acidic urine, and may cause renal damage. Major route of elimination – kidneys.

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MECHANISM OF ACTION – form covalent bonds with nucleophilic sites on nucleic acid, phosphate, amino acid and proteins through the formation of carbonium ion which attack the N7 POSITION OF GUANINE THIS LEADS TO DNA MISREADING , ABNORMAL BASE PAIRING , DNA INTERSTRAND CROSS LINKING AND DNA STRAND BREAKAGE

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TOXICITY : adrenal insufficiency pulmonary fibrosis and skin pigmentation

STREPTOZIN- has high affinity for beta cells of islet of langerhans of pancreas

10. DACARBAZINE –used in treatment regimen in hodgkins disease as part of the abvd regimen(adriamycin, bleomycin, vinblastine,decarbazine) ALKYLATING AGENTS A. NITROGEN MUSTARD : 1. MECHLORETHAMINE 2. CHLORAMBUCIL 3. CYCLOPHOSPHAMIDE 4. MEPHALAN 5. IFOSFAMIDE B. NITROSOUREAS 1. LOMUSTINE 2. CARMUSTINE 3. STRETOZOCIN C.

D. E. F. 1.

TRIAZINES DACARBAZINE ALKYL SULFONATE : BUSULFAN PLATINUM DERIVATIVE CISPLATIN CARBOPLATIN METHYLHYDRAZINE PROCARBAZINE

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TOXICITY : hemorrhagic cystitis (prevention of this is by vigorous hydration and the use of mercaptoethanesulfonate (mesna)) -cardiac dysfunction, pulmonary toxicity

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Causes also single stranded breaks in DNA

(Similar to Dactinomycin). It inhibits the synthesis of DNA dependent RNA synthesis

Toxic specific for asteoclasts and lowers serum calcium

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focus a complex with DNA involving selective binding to and intercalation between the guanine-cytosine segments

Bleomycin Sulfate – derive from S. Verticillus. -

It is antitumor, anti viral and anti bacterial. It is a mixture of different copper chelating glycopeptide

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Binds with DNA to produce single & double stranded breaks

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DNA is cleaved at guanine-cytosine and guanine-thymine seq.

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a. Doxorubicin (adriamycin) b. Daunorubicin

Are anthracycline antibiotics

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Mech. Of Action:

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IFOSFAMIDE – A DERIVATIVE OF CYCLOPHOSPHAMIDE

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CARMUSTINE (BCNU) AND LOMUSTINE (CCNU) • ARE NITROSOUREAS WITH HIGH LIPOPHILICITY THAT FACILITATES CNS ENTRY • USE –TREATMENT OF BRAIN TUMORS

Intercalation in the DNA – the drug inserts between adjacent base pairs and binds to sugar- PO4 backbone of DNA, thus blocking DNA synthesis

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Binds to cell membrane and alters the function of transport process

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Generation of Oxygen radicals or superoxide

CISPLATIN AND CARBOPLATIN • Cisplatin is given intraveneously, cleared unchanged by the kidney

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USE – component in the treatment regimen for testicular carcinoma, cancers of the bladder, lung and ovary. TOXICITY : git distress ,mild hematoxicity ,but neurotoxic (pheripheral neuritis and acoustic nerve damage )and nephrotoxic . renal damage may be reduce by the use of mannitol and forced hydration . Carboplatin is less nephrotoxic ,less likely to cause tinnitus and hearing loss but has a greater myelosuppresant actions

PROCARBAZINE –

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Plicamycin(Mithramycin) – comes from Streptomyces plicatus.

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A nitrogen mustard that is biotransformed by the hepatic cychrome p450 into hydroxylated intermediates : phosphoramide , the active alkylating agent (anti- cancer) and acrolein which can cause hemorrhagic cystitis

CHLORAMBUCIL – SLOWEST ACTING ALKYLATING AGENT

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coverted spontaneously into a reactive cytotoxic product. acts on all phase but most sensitive is G1 and S PHASE CLINICAL USES : use in combination with other anti cancer agents in the MOPP regimen(Mechlorethamine, Oncovin or Vincristine, Procarbazine, Prednisone

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Dactinonomycin (Actinomycin D)

CYCLOPHOSPHAMIDE

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MECHLORETHAMINE

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III -Antibiotics – Binds to DNA by intercalation. Inhibit DNA or RNA synthesis cycle phase non specific

MECH OF ACTION =a reactive agent that forms hydrogen peroxide ,which generates free radicals that cause dna strand scission orally active, penetrates most tissues ,including csf. eliminated via hepatic metabolism USE= component of mopp regimen for the treatment of hodgkins disease TOXICITY =myelosuppresant ,git irritation ,cns dysfunction, peripheral neuropathy and skin reactions . can cause a disulfiram like reaction with ethanol , it is also leukemogenic

BUSULFAN –AN ALKYL SULFONATE

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USE = treatment regimen for myelogenous leukemia

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Mitomycin - comes from Streptomyces Calspitosus contains quinone, a urethane and an aziridine

IV – Plant derivatives 1. Vinca Alkaloids a. Vinblastine b. Vincristine Source: periwinkle plant (vinca rose) - Both cycle and phase specific Mitotic spindle

Active most in cell cycle in late G and early S phase. Potentiates cardiotoxic effect of Doxorubicin

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Block mitosis in Metaphase Binds to Tubulin inhibit assembly of microtubules thus the failure of mitotic spindle cells in S phase are most sensitive

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Epipodophylltoxins Etoposide (VP-16) Teniposide (VM-26) Synthetic derivatives of the extract of the American mandrake plant

Taxanes: Paclitaxel, docetaxel Given IV--Clinical use: used in advanced breast and ovarian cancers

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Appears to arrest cells in G2 phase

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Cause dose dependent break on DNA strands

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Probably act through inhibition of DNA topoisomerase II

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are spindle poisons but act differently from vinca alkaloids. They prevent microtubule disassembly into tubulin monomers

Toxicity: Paclitaxel: causes neutropenia, thrombocytopenia, a high incidence of peripheral neuropathy and possible hypersensitivity reactions during infusion. Docetaxel: neurotoxicity and BMS

V – Miscellaneous Agent Mechanism of Action 1.

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Amsacrine

2. Asparaginase (LAsparaginase)

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cytotoxic, binds to DNA through intercalation and has base specificity on A-T pairs

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more effective in cycling cells

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Hydrolyzes blood asparaginase which is necessary for growth and function of cells, thus tumor cells are deprived of this nutrient required for protein synthesis.

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Rifuximab = a monoconal antibody to a surface protien in HodgKins lymphoma cells. Trastuzumab = is a monoclonal antibody to a surface protien in breast cancers that overexpress the HER2 protien. Can cause cardiac dysfunction, including CHF Therapeutic Usefulness:

1. Methotrexate

ALL, chorio CA, BukKitts Lymphoma in Children, breast, neck and head CA

2. 6 Mercaptopurine

ALL (acute Lymphoblastic Leukemia)

3. 6 THioguanine

Acute myelocytic leukemia

4. 5 Fu

CA of colon, breast, ovarian, pancreatic, gastric CA

5. Cytarabine

Acute myclogenous leukemia.

6. Dactinomycin

Wilm’s tumor, chorio CA, soft tissue sarcomas

7. Doxorubicin

ALL, HodgKins, breast and Lung CA

8. Daunorubicin

AML

9. Bleomycin

Testicular tumors (w) vinblastine and cisplatin

10. Plicamycin

Bone tumor

11. Mechlorethamine

HodgKin (MOPP regimen Mechlorethamine, Oncovin, Prednisone, Procarbazine)

12. Cyclophosphamide

BurKitts and Breast CA lymphoma

13.Lomustine/Carmustine

malignant glioma

14. Vincristine

ALL, Wilms tumor, Ewings, Soft tissues sarcoma and HodgKins

15. Vinblastine

testicular CA, Hodgkin

16. Dacarbazine)

malignant melanoma Hodgkins (combine with Doxorubicin)

17. Streptozocin

Pancreatic cell carcinoma

18. Etoposide

Oat cell carcinoma of lungs

Treatment Choices for Cancer responsive to Systemic Agents 1. Acute lymphocytic leukemia (ALL)

Vl – Hormones – mainly Palliative Antagonize or lower concentration of normally occuring hormones in hormone dependent tumors 1. Adrenocorticosteroids – useful in acute leukemia in children and malignant lymphoma. 2. Aminogluthethimide (cytadren) inhibits synthesis of adrenocorticosteroids when administered with hydrocortisone can effectively reduce estradiol levels useful in advanced carcinoma of the breast (estrogenreceptor(+) tumors 3. Mitotane(O,P –DDD) (Lysodren) Selectively attacks adrenocortical cells use in palliative treatment of inoperable adrenocortical carcinoma 4. Progestins– useful in the management of endometrical CA. (Hydroxy Progesterone Megestrol) 5. Estrogens – use to treat prostatic CA. (estradiol, diethylstilbesterol) Estramustine – a nitrogen mustard linked to estradiol, use as a palliative treatment of advanced prostatic carcinoma. 6. Androgens - use to treat carcinoma of the breast in both premenopausal and past menopausal women. (Testosterone fluoxymesterone) 7. Tamoxifen – antiestrogen – competes with estrogen for binding with receptor - use in CA of breast, estrogen(+) receptors 8. Gonadotropin – reduces circ. Gonadotropins and testosterone. Effective in prostatic carcinoma. VII- Aromatase Inhibitors: Anastrozole and letrozole inhibit aromatase, the enzyme that catalyzes the conversion of androstenedione (an androgenic precursor) to estrone (an estrogenic hormone) Uses: Advanced breast cancer Toxicity: Nausea, diarrhea, hot flashes, bone and back pain, dyspnea and peripheral edema. VIII- Monoclonal Antibodies:

For Remission: maintenanceMethotrexare, Thioguanine

Induction: Combination Chemo Adults: Vincristine, Prednisone, Daunorubicin,Asparagin ase For children: w/o aspaginase

2. Acute Myelocytic and myelomonocytic leukemia

Combination Chemo

3. Chronic Myelocytic leukemia

Hydroxyurea; alpha interferon (Busulfan,

Cytarabine Daunorubicin or idarubicin

Mercaptopurine, thioguanine, cytarabine,plicamycin) 4. Chronic lymphocytic leukemia

Chlorambucil+ Prednisone or fludarabine

5. Hairy cell

Alpha interferon cladribine

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Combination Chemo (ABVD)

HodgKins dis (stages III & IV)

Combination Chemo (MOPP)

1. Doxorubicin (Adriamycin) 2. Bleomycin

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Mechlorethamine

3. Vinblastin

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Vincristine

4. Dacabazine

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Prednisone

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4. Procarbazine

7. Non HodgKins lymphoma

Combination Chemotheraphy - Cyclophosphamide - Vincristine - Doxorubicin - Prednisone

8.Multiple Myeloma

Combination Chemotherapy - Melaphalan + Prednisone or 1. Melaphalan

9. Waldenstrom's Macroglobulinemia

2. Cyclophosphamide

15. Vinblastine

- BMS

3. Carmustine

16. Progesterone

- fluids retention, hypertension

4. Vincristine

17. Tamoxifen

- nausea and vomiting

5. Doxorubicin

18. Estrogen

- thromboembolic accidents

6. Prednisone

19. Busulfan

- skin pigmentation, pulmonary fibrosis, adrenal insuffiency

20. Cisplastin

- Nephrotoxicity (renal toxicity) and acoustic nerve dysfunction

2. Vincristine

21. Procarbazine

- BMS, CNS depression

3. Prednisone

22. L-asparaginase

- Allergic reactions, fever, pancreatitis, thrombocytopenia

23. Etoposide

BMS, allergic reaction

24. Fluoxmesterone

- Cholestatic jaundice

Chlorabucil or Combination Chemotherapy 1.Cyclophosphamide

10. Polycythemia Vera

Hydroxyurea

11. carcinoma of Lung (small cell)

Combination Chemotherapy Cisplatin and etoposide (palliative – Radiation)

12. Non-small cell Lung CA 113. Carcinoma of the head and neck 14. Carcinoma of the Esophagus

Advance – Cisplatin + Vinorelbine Localized – Cisplatin + Vinblastin Combination Chemotherapy 1. Cisplatin and 5 FU Combination Chemotherapy 1. 5 FU 2. Cisplatin

15. Carcinoma of the Stomach and Pancreas

16. Carcinoma of the colon

Principles of Combination Therapy 1. Each drug should be active when used alone against the particular cancer. 2. The drugs should have different mechanism of action. 3. Cross – resistance between drugs should be minimal. 4. The drugs should have different toxic effects. Combination Chemotherapy 1. HodgKin's disease a. MOPP regimen Mechlorethamine, Oncovin (vincristine), Procarbazine, Prednisone b. ABVD regimen, Adriamycin, (Doxorubicin) Bleomycin, Vinblastine, Decarbazine

Stomach – Etoposide: 5FU w/ leucovorin (ELF)

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Non-Hodgkins Lymphoma COP regimen – Cyclophosphamide, Oncovin, Prednisone

Pancreas – 5 FU or ELF

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Testicular Cancer – PVB regime, Plationol, Vinblastine, Bleomycin

Colon - Fuorouracil + levamisole (adjuvant) or w/ leucovorin

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Rectum – 5FU w/ radiation therapy (adjuvant) 17. Carcinoma of the kidney

Vinblastine

18.Carcinoma of the bladder

Combination Chemotherapy

Breast Cancer CMF regimen – Cyclohosphamide, Methotrexate, Fluorouracil with or without Tamoxifen b. CAF – in which Adriamycin(Doxorubicin) replaces Methotrexate a.

Additional Strategies for cancer Chemotherapy

1. 1. Methotrexate 2.Vinblastine 3. Doxorubicin

4. Cisplatin CMF regimen: Cyclophosphamide plus 19. Breast Carcinomamethotrexate& fluoouracil, or doxorubicin (stages I &II) for methotrexate CAF regimen: tamoxifen if hormone receptor positive 20. Breast carcinoma (stages III & IV)

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- As above paclitaxel, plus trastuzumab(if HER2 protein) w/ or w/o aromatase inhibitors

Pulse therapy – involves intermittent treatment with very high doses of an anti-cancer drug-are too toxic to be used continuously. Intensive drug treatment is every 3-4 weeks. This type of regimen is used in therapy of: 1. acute leukemia 2. testicular CA 3. Wilms tumor Recruitment and Synchrony – the strategy of recruitment involves initial use of CCNS drug to achieve a significant log kill, which results in the recruitment into cell division of previously resting cells in the GO phase. With subsequent administration of CCS drug that is achieve against dividing cells. Syncrony – example the use of vinca alkaloids to holds cancer cell in the M phase and subsequent treatment of another CCS drug such as the S-phase specific Cytarabine which results in a greater killing effect on the neoplastic cell population

Dose limiting adverse effects of Chemotherapetic agents 1. Methotrexate

- Bone marrow suppression (BMS) - oral and GI ulceration - acute renal failure - hepatotoxicity

2. 6 Mercaptopurine

- BMS, oral and GI ulcers

3. 6 Thioguanine

- BMS

4. 5 FU

- BMS, oral and GI ulcers dacryocystitis

5. Cytarabine

- BMS, CNS toxicity

6. Dactinomycin

- BMS, stomatitis, oral ulcers

7. Doxorubicin

- BMS, cardiotoxicity

8. Bleomycin

- Pneumonitis, pulmonary fibrosis

9. Plicamycin

- BMS, hemorrhagic cystitis

10. Mitomycin

- BMS, trombocytopenia, leukopenia

11. Mechlorethamine

- BMS

12. Cyclohosphamide

- BMS, hemorrhagic cystitis

13. Nitrosoureas

- Thrombocytopenia, leukopenia

14. Vincristine

- Peripheral neuropathy

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Rescue Therapy – use to alleviate toxic effects of anticancer drugs.

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Leucovorin – bypasses the dihydrofolate steps reductase in folic acid synthesis thus reducing toxicity of antifolate agents. Mercaptoethanosulfonate(mesna) - “Traps” acrolein released from Cyclophosphamide thus reducing hemorrhagic cystitis. Dexrazoxane – a free radical “trapper” that protect against cardiac toxicity due to anthracyclines (doxorubicin)