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CANCER CHEMOTHERAPY Principles of Cancer ChemotherapyGoal of treatment
A.Cure – eradication of every neoplastic cellB.Palliation – alleviation of symptoms and avoidance of lifethreatening toxicity
Tumor susceptibility and the growth cycle4 Phases of the Cell Cycle
1.M phase – period of mitosis (cell division)2.G1 phase – interval during which RNA, protein synthesis andcellular growth occurs3.S phase – DNA synthesis4.G2 phase – synthesis of cellular components required formitosis5.Go- resting state where cell is not dividing
2 Types of Cancer Chemotherapeutic Agents base on its effect oncell cycle
1.
Cell – cycle specific drugs – drugs that inhibit cell replicationduring a phase of a cycle.Example: Methotrexate – inhibits DNA synthesis during S-phase(Antimetabolite)Others: Bleomycin, Antibiotics, Vinca Alkaloids- They are effective for Cancer with a high growth fraction (e.g –hematologic cancers)
2.
Cell-cycle non specific – agents that are active while the cancercells are dividing but whose action spans more than one phaseof the cycle as well as within Go.
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Example: Mechlorethamine, cisplatin, nitrosourceas
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they are effective for both high growth fraction aswell 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 (except5FU) They act in 2 ways:a.By incorporation into a metabolite pathway andformation of a false metaboliteb.By inhibition of the catalytic function of an enzyme orenzyme systemAntimetabolitea)Folate antagonist : Methotrexate, Trimetrexateb)Purine derivatives : Mercaptopurine ,Thioguaninec)Pyrimidine derivative : Fluorouracil (5 FU), Floxuridine,Cytarabine
1.Methotrexate
Mechanism of Action – competes with folic acid for the activebinding sites on dihydrofolate reductase (DHFR) enzymePharmacokinetic:-converted to polyglutamated metabolite which alsoinhibits DHFR-also converted to a 7-OH derivative byhydroxylation – less water soluble – may lead tocrystalluria in acidic urine, and may cause renaldamage. Major route of elimination – kidneys.
2.Trimetrexate
-antimalarial agent, also a potent inhibitor of DNHFR
3.6 – Mercaptopurine
-the thiol analog of the purine hypoxanthine. It is convertedto the corresponding nucleotide – 6-thioinosinic acid 6 T-IMP which inhibits the formation of adenine and guaninefrom Inosinic monophosphate (IMP).-Fate: 6 MP is converted to thiouric acid in the liver (thisreaction is catalyzed by xanthine oxidase)
4.6- Thioguanine (6 TG)
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MECH = converted to 6 –thioguanine 5 Phosphate (6-thio-GMP) which replace guanine nucleotide and inhibit DNAsynthesis
5.
Fluorouracil (5 FU)
Inhibits thymidylatesynthetase thus interferes DNA production
6.Floxuridine (FUDR or 5 FUDR)
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MECH= 5 FU is a pyrimidine analog. Interferes theconversion of deoxyuridylic acid to thymidylic acid.
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5 FU must be converted to 5 FdUMP-( 5 Fluorodeoxyuridinemonphosphate,) which competes with deoxyuridinemonophosphate for the enzyme thymidylate synthetase.
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5 FU is metabolized in the liver to CO2 which is thenexpired.
7.CYTARABINE ( CYTOSINE ARABINOSIDE, ARA –C)
Analog of 2 –deoxycytidine
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S- CYCLE SPECIFIC
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MECHANISM OF ACTION –an pyrimidineantimetabolite ,phoshorylated to the active cytotoxicnucleotide cytosine arbinase triphosphate, aninhibitor of DNA polymerase
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Given parenterally ,not orally because it isdeaminated to a noncytotocic product in the intestinalmucosa
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uses – is an imporatnt component for the treatmentof acute leukemias
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 Toxicities – GIT irritation , myelosuppresion ,neurotoxicity (cerebellar dysfunction and peripheralneuritis)
II. ALKYLATING AGENTS
 
–are cycle phase nonspecific
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MECHANISM OF ACTION – form covalent bonds with nucleophilicsites on nucleic acid, phosphate, amino acid and proteinsthrough the formation of carbonium ion which attack the N7POSITION OF GUANINE
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 THIS LEADS TO DNA MISREADING , ABNORMAL BASE PAIRING ,DNA INTERSTRAND CROSS LINKING AND DNA STRANDBREAKAGE
 
ALKYLATING AGENTSA.NITROGEN MUSTARD :
1.MECHLORETHAMINE2.CHLORAMBUCIL3.CYCLOPHOSPHAMIDE4.MEPHALAN5.IFOSFAMIDE
B.NITROSOUREAS
1.LOMUSTINE2.CARMUSTINE3.STRETOZOCIN
C.TRIAZINES
DACARBAZINE
D.
ALKYL SULFONATE :
BUSULFAN
E.PLATINUM DERIVATIVE
CISPLATINCARBOPLATIN
F.METHYLHYDRAZINE
PROCARBAZINE
 1.MECHLORETHAMINE
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coverted spontaneously into a reactive cytotoxic product.acts on all phase but most sensitive is G1 and S PHASE
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CLINICAL USES : use in combination with other anti canceragents in the MOPP regimen(Mechlorethamine, Oncovin orVincristine, Procarbazine, Prednisone
2.CYCLOPHOSPHAMIDE
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A nitrogen mustard that is biotransformed by the hepaticcychrome p450 into hydroxylated intermediates :phosphoramide , the active alkylating agent (anti- cancer)and acrolein which can cause hemorrhagic cystitis
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 TOXICITY : hemorrhagic cystitis (prevention of this is byvigorous hydration and the use of mercaptoethanesulfonate (mesna))-cardiac dysfunction, pulmonary toxicity
3.
CHLORAMBUCIL
– SLOWEST ACTING ALKYLATING AGENT
4.
IFOSFAMIDE
– A DERIVATIVE OF CYCLOPHOSPHAMIDE
5.CARMUSTINE (BCNU) AND LOMUSTINE (CCNU)
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ARE NITROSOUREAS WITH HIGH LIPOPHILICITY THATFACILITATES CNS ENTRY
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USE –TREATMENT OF BRAIN TUMORS
6.CISPLATIN AND CARBOPLATIN
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Cisplatin is given intraveneously, cleared unchanged bythe kidney
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USE – component in the treatment regimen for testicularcarcinoma, cancers of the bladder, lung and ovary.
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 TOXICITY : git distress ,mild hematoxicity ,but neurotoxic(pheripheral neuritis and acoustic nerve damage )andnephrotoxic . renal damage may be reduce by the use of mannitol and forced hydration .
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Carboplatin is less nephrotoxic ,less likely to cause tinnitusand hearing loss but has a greater myelosuppresantactions
7.PROCARBAZINE –
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MECH OF ACTION =a reactive agent that forms hydrogenperoxide ,which generates free radicals that cause dnastrand scission
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orally active, penetrates most tissues ,including csf.eliminated via hepatic metabolism
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USE= component of mopp regimen for the treatment of hodgkins disease
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 TOXICITY =myelosuppresant ,git irritation ,cns dysfunction,peripheral neuropathy and skin reactions . can cause adisulfiram like reaction with ethanol , it is alsoleukemogenic
8.
BUSULFAN
–AN ALKYL SULFONATE
•
USE = treatment regimen for myelogenous leukemia
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 TOXICITY : adrenal insufficiency pulmonary fibrosis andskin pigmentation
9.
STREPTOZIN
- has high affinity for beta cells of islet of langerhans of pancreas
10.
DACARBAZINE
–used in treatment regimen in hodgkinsdisease as part of the abvd regimen(adriamycin, bleomycin,vinblastine,decarbazine)
III -Antibiotics – Binds to DNA by intercalation.Inhibit DNA or RNA synthesis cycle phase non specific
1.Dactinonomycin(Actinomycin D)
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focus a complex withDNA involving selectivebinding to andintercalation betweenthe guanine-cytosinesegments
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Causes also singlestranded breaks in DNA2.Plicamycin(Mithramycin) –comes from Streptomycesplicatus.
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 Toxic specific forasteoclasts and lowersserum calcium(Similar to Dactinomycin). Itinhibits the synthesis of DNAdependent RNA synthesis3.Bleomycin Sulfate – derivefrom S. Verticillus.
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It is antitumor, antiviral and anti bacterial.It is a mixture of different copperchelating glycopeptide
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Binds with DNA toproduce single & doublestranded breaks
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DNA is cleaved atguanine-cytosine andguanine-thymine seq.4.a. Doxorubicin(adriamycin)b. Daunorubicin
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Are anthracycline antibioticsMech. Of Action:
1.
Intercalation in the DNA – the drug inserts betweenadjacent base pairs and binds to sugar- PO
4
backboneof DNA, thus blocking DNA synthesis2.Binds to cell membrane and alters the function of transport process3.Generation of Oxygen radicals or superoxide5.Mitomycin - comes fromStreptomycesCalspitosus containsquinone, a urethane andan aziridine
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Active most in cell cycle inlate G and early S phase.Potentiates cardiotoxiceffect of Doxorubicin
IV – Plant derivatives
1.Vinca Alkaloidsa.Vinblastineb.VincristineSource: periwinkle plant (vincarose)- Both cycle and phasespecific Mitotic spindle
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Block mitosis inMetaphase
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Binds to Tubulin inhibitassembly of microtubules thus thefailure of mitotic spindle
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cells in S phase aremost sensitive
 
2.Epipodophylltoxins
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Etoposide (VP-16)
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 Teniposide (VM-26)
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Synthetic derivatives of the extract of theAmerican mandrakeplant
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Appears to arrest cellsin G2 phase
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Cause dose dependentbreak on DNA strands
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Probably act throughinhibition of DNAtopoisomerase II3.Taxanes: Paclitaxel,docetaxel Given IV---Clinical use: used inadvanced breast andovarian cancers
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are spindle poisons butact differently fromvinca alkaloids. Theyprevent microtubuledisassembly intotubulin monomers
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 Toxicity:
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Paclitaxel: causes neutropenia, thrombocytopenia, a highincidence of peripheral neuropathy and possiblehypersensitivity reactions during infusion.
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Docetaxel: neurotoxicity and BMS
V – Miscellaneous Agent
Mechanism of Action1.Amsacrine
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cytotoxic, binds to DNA throughintercalation and has base specificityon A-T pairs
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more effective in cycling cells2.2. Asparaginase(L-Asparaginase)
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Hydrolyzes blood asparaginase whichis necessary for growth and functionof cells, thus tumor cells aredeprived of this nutrient required forprotein synthesis.
Vl – Hormones – mainly Palliative
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Antagonize or lower concentration of normally occuring hormonesin hormone dependent tumors1.Adrenocorticosteroids – useful in acute leukemia in children andmalignant lymphoma.2.Aminogluthethimide (cytadren)
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inhibits synthesis of adrenocorticosteroids
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when administered with hydrocortisone can effectivelyreduce estradiol levels
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useful in advanced carcinoma of the breast (estrogen-receptor(+) tumors3.Mitotane(O,P –DDD) (Lysodren)
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Selectively attacks adrenocortical cells
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use in palliative treatment of inoperable adrenocorticalcarcinoma4.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 apalliative treatment of advanced prostatic carcinoma.6.Androgens - use to treat carcinoma of the breast in bothpremenopausal and past menopausal women. (Testosteronefluoxymesterone)7.Tamoxifen – antiestrogen – competes with estrogen for bindingwith receptor- use in CA of breast, estrogen(+) receptors8.Gonadotropin – reduces circ. Gonadotropins and testosterone.Effective in prostatic carcinoma.
VII- Aromatase Inhibitors:Anastrozole and letrozole
inhibit aromatase, the enzyme that catalyzesthe 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 andperipheral edema.
VIII- Monoclonal Antibodies:
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Rifuximab
= a monoconal antibody to a surface protien inHodgKins lymphoma cells.
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Trastuzumab
= is a monoclonal antibody to a surface protienin breast cancers that overexpress the HER
2
protien. Can causecardiac dysfunction, including CHF
Therapeutic Usefulness:
1. Methotrexate ALL, chorio CA, BukKitts Lymphomain Children, breast, neck and headCA2. 6 Mercaptopurine ALL (acute Lymphoblastic Leukemia)3. 6 THioguanine Acute myelocytic leukemia4. 5 FuCA of colon, breast, ovarian,pancreatic, gastric CA5. CytarabineAcute myclogenous leukemia.6. DactinomycinWilm’s tumor, chorio CA, soft tissuesarcomas7. DoxorubicinALL, HodgKins, breast and Lung CA8. Daunorubicin AML9. Bleomycin Testicular tumors (w) vinblastineand cisplatin10. Plicamycin Bone tumor11. Mechlorethamine HodgKin (MOPP regimenMechlorethamine, Oncovin,Prednisone, Procarbazine)12. Cyclophosphamide BurKitts and Breast CA lymphoma13.Lomustine/Carmustine malignant glioma14. Vincristine ALL, Wilms tumor, Ewings, Softtissues sarcoma and HodgKins15. Vinblastine testicular CA, Hodgkin16. Dacarbazine) malignant melanomaHodgkins (combine withDoxorubicin)17. Streptozocin Pancreatic cell carcinoma18. Etoposide Oat cell carcinoma of lungs
Treatment Choices for Cancer responsive to Systemic Agents
1. Acute lymphocyticleukemia (ALL)For Remission:maintenance-Methotrexare, ThioguanineInduction: Combination ChemoAdults: Vincristine, Prednisone,Daunorubicin,AsparaginaseFor children: w/o aspaginase2. Acute Myelocytic andmyelomonocyticleukemiaCombination ChemoCytarabine Daunorubicin oridarubicin3. Chronic MyelocyticleukemiaHydroxyurea; alpha interferon(Busulfan,Mercaptopurine, thioguanine,cytarabine,plicamycin)4. Chronic lymphocyticleukemiaChlorambucil+ Prednisone orfludarabine5. Hairy cell Alpha interferon cladribine6.HodgKins dis(stages III & IV)Combination Chemo(MOPP)1.Mechlorethamine2.Vincristine3.Prednisone4.4. ProcarbazineCombination Chemo (ABVD)1. Doxorubicin (Adriamycin)2. Bleomycin3. Vinblastin4. Dacabazine7. Non HodgKinslymphomaCombination Chemotheraphy- Cyclophosphamide- Vincristine- Doxorubicin- Prednisone8.Multiple Myeloma Combination Chemotherapy- Melaphalan + Prednisone or1. Melaphalan
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