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MARVIN
FRIEDMAN, Pharm.D. PHARMACOLOGY
OF CHEMOTHERAPEUTIC AGENTS I.
Review of cellular metabolism 1.
Purine and pyrimidine synthesis 2.
Attachment of ribose sugar to form ribonucleotides 3. Formation of
ribonucleotides to form DNA II. DNA Review 1.
Double helix structure 2.
Thymine (pyrimidine) binds to adenine (purine) Cytosine (pyrimidine)
binds to guanine (purine) 3.
Composed of chromosomes that direct cellular life 4. Directs
formation of RNA III. RNA review 1.
Made from DNA template Adenine = Uracil Guanine = Cytosine
Thymine = Adenine Cytosine = Guanine 2. Migrates to
ribosomes to direct formation of protein IV. Protein Synthesis Review 1.
Every 3 RNA molecules are read as an amino acid 2.
Amino acids make up protein |
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Page
2 CANCER CELL
CYCLE 1.
S Phase
a. Replicating phase
b. Most cytotoxic drugs work here 2.
G2 Phase a.
Specific protein synthesis for division 3.
M Phase a.
Mitosis b.
Plant alkaloids prevent mitosis 4.
G Phase a.
Non dividing but retains
capacity to divide 5.
G1 Phase a.
Precursors for DNA made b.
Longest phase of division DRUG
RESISTANCE 1.
Innate 2.
Acquired a.
Decrease drug uptake (eg. Nitrogen Mustard) b.
Increase catabolism of drug (eg. 6‑MP) c.
No enzyme to activate drug (eg 5‑FU) d.
Quantitative change in target (eg. MTX high dose) GENERAL
PRINCIPLES 1.Drugs
Kill by first order kinetics a.
Effective drug kills 99.9% of tumor cells (equivalent to 31og kill) 2.
Importance of schedule of administration 3.
Importance of differential cell killing 4.
Advantage of combination therapy TABLE 1: Number of 100 percent effective 10' log Number of
kills necessary to reduce the tumor cell burden to
one cell (theoretical) Cancer Cells
Clinical Log
% Cells (Iogarlthmic scale) Event
Kill 10"
= 10 kg.
Death
101
Surviving Cells Killed
Number Killed 10'Z
‑ 1
kg. Severe
Metastatic Disease
Start 1,000,000,000,000 10"
= 100 gm. Advanced
Metastases
1 100,000,000,000 90
900,000,000,000 1010
= 10 gm.
Regional Spread of Cancer
2
10,000,000,000
90 90,000,000,000 109
= 1 gm.
Clinical Detection (Symptoms)
3
1,000,000,000 90
9,000,000,000 108
= 100 mg. Subclinical
Disease
4
100,000,000 90
900,000,000 106
= 1 mg.
Subclinical Disease
5
10,000,000 90
90,000,000 10'
= 1 mcg.
Carcinoma in situ
6
1,000,000
90
9,000,000 10'
= 1 ng.
Neoplastic Transformation
7
100,000
90
900,000
8
10,000
90
90,000
9
1,000
90
9,000
10
100
90
900
11
10 90
90
12
1 90
9 |
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ALKYLATING
AGENTS I.
Introduction
A. Action 1.
Cell cycle nonspecific 2.
Causes abnormal base pairing of DNA strands 3.
Cytotoxic and mutagenic effect 4.
Inhibit glycolysis, respiration, and various enzyme protein and
nucleic acid synthesis. B.
Toxicities 1.
Normal tissues affected are those with rapid growth rate;
hematopoietic system, GI tract and gonads. 2.
Extravasation will cause tissue necrosis and skin sloughing. II.
Alkylating A.
Mechlormethamine (Mustargen) 1.
Disposition
a. Must be given IV 2. Toxicities
a. Bone marrow depression ocurs slowly and recovers in 4‑6
weeks; dose limiting b. Lymphocytopenia is evident within 24 hours. c.
Emesis 3.
Use: Breast CA, Hodgkin's, Lung CA, lymphoma. B.
Cyclophosphamide (Cytoxan) 1.
Disposition
a. Given orally or parenterally
b. Relatively slow onset of activity
c. Metabolized in liver
d. Excreted in feces 2.
Toxicities
a. Hemorrhagic cystitis
b. Alopecia 3.
Uses: Lymphoma, ALL, CLL, multiple myeloma, Breast CA C.
Melphalan (Alkeran) 1.
Disposition: Oral or parenteral administration 2.
Does not produce alopecia 3.
Use: Multiple myeloma, Breast CA D.
Chlorambucil (Leukeran) 1.
Disposition: oral administration 2.
Slowest acting and least toxic 3.
Moderate myelosuppression 4.
Therefore drug that elderly can withstand 5.
Use: CLL, Breast CA, Hodgkins, Ovarian CA, Testicular CA E.
Busulfan (Myleran) 1.
Disposition: Administer Orally 2.
Selective effect on maturing bone marrow
‑ Low doses depress granulopoiesis and platelet formation
‑ High doses depress erythropoisis 3.
Lymphocytes not destroyed 4.
Not cytotoxic to GI tract 5 Use: CGL 6.
Toxicity: Thrombocytopenia, hyperuricemia |
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Nitrosoureas A. Introduction 1. Effective against CNS tumors 2. Not cell cycle specific 3. Produce metabolites which alkylate nucleic acids and proteins B. Carmustine (BCNU) 1. Disposition: IV administration 2. Use: Brain CA, Breast CA, Colon CA, Hodgkin's, Lung CA 3. Toxicity a. Nausea and vomiting within 2 hours b. Delayed bone marrow suppression (3‑6 weeks after administration) C. Lumustine (CCNU), Semustine (MeCCNU) 1. Disposition: oral administration 2. Use: Hodgkin's 3. Toxicities: Delayed bone marrow suppression |
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MISCELLANEOUS I.
Cisplatin (Platinol) 1.
Disposition a.
IV administration b.
Excreted unchanged in urine c.
Distributes to all tissues except brain 2.
Action a.
Not cell cycle specific b.
DNA synthesis is markedly inhibited and remains depressed for
prolonged periods c.
Intrastrand crosslinking of DNA 3.
Use: Bladder CA, Testicular CA, Ovarian CA 4.
Toxicities
a. Nausea/vomiting relieved by marijuana
b. Nephrotoxicity
c. Ototoxicity
d. Moderate myelosuppression II.
L‑Aspariginase 1.
Hydrolyzes L‑asparagine to aspartic acid 2.
Effective against malignant lymphoblasts which have an absolute
requirement for
exogenous L‑asparagine 3.
Use: ALL 4.
Toxicities: Allergic, CNS disturbance 5.
Resistance: Cells not requiring L‑asparagine |
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ANTITUMOR
ANTIBIOTIC I.
Action 1.
Interfere with nucleic acid synthesis 2.
Intercalates adjoining nucleotide pairs of the DNA helix 3.
Block DNA directed RNA and DNA transcription 4.
Effect cells in G2 also II.
DOXORUIN (Adriamycin), DAUNOMYCIN
(Cerubidine) 1.
Disposition a.
Administered intravenously b.
Metabolized in liver and excreted in bile 2.
Toxicity a.
Bone marrow aplasia ‑ nadir 2 weeks b.
Delayed cardiotoxicity ‑ binds to myocardial DNA 3.
Uses a.
Daunomycin: AML, ALL b.
Adriamycin: Sarcoma, Breast CA, Lung CA, Malingnant lymphoma 4.
Extravasation causes necrosis of tissue and sloughing III.
MITHRAMYCIN (Mithracin) 1.
Disposition a.
Administered intravenously b.
Excreted in urine 2.
Toxicity a.
Hemorrhagic syndrome ‑ heralded by facial flushing b.
Liver and kidney toxicity c.
GI toxicity d.
Bone marrow toxicity not significant 3.
Uses
a. Hypercalcemia IV.
BLEOMYCIN (Blenoxane) 1.
Action a.
DNA strand breakage b.
G2 and M phase specific 2.
Toxicity a.
Dose related pneumonitis b.
Minimal bone marrow suppression 3.
Use a.
Epidermoid carcinomas of hand, neck, GU b.
Hodgkins ANTIMETABOLITES I.
Introduction 1.
Activity during S phase 2.
Effective against tumors that have a high growth fraction 3.
Analogues of naturally occuring metabolites 4. Falsely
substituting for purines and pyrimidines II. METHOTREXATE (Mexate) 1. Action a.
Irreversibly binds to dihydrofolate reductase b.
Inhibition of purine biosynthesis c.
Inhibition of pyrimidine biosynthesis |
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2.
Disposition
a. Administration: intravenous, intrathecal
b. Does not cross blood brain barrier
c. excreted in urine 3.
Toxicity a.
GI ulceration b.
Bone marrow aplasia ‑ nadir 1‑2 weeks 4.
Use a.
ALL b.
Choriocarcinoma 5.
Miscellaneous
a. High dose necessary in resistant cells then leucovorin
(activated folic acid) rescue given a few hours later III. PURINE
ANTAGONISTS A.
6‑MERCAPTOPURINE (Purinethol), 6‑THIOGUANINE (Thioguanine) 1.
Action a.
Inhibit purine biosynthesis after metabolism to the nucleotide b.
False metabolite that interferes with DNA and RNA synthesis 2. Resistance:
Secondary to low levels of enzymes necessary to convert to
nucleotied 3. Disposition a.
Administration: orally b.
Mostly metabolized 4. Drug
Interaction a.
Allopurinol with 6‑MP 5. Toxicity a.
Bone marrow depression 6. Use: ALL,
AML B.
AZATHIOPRINE (Imuran) 1. Action:
metabolized to mercaptopurine 2. Disposition a.
Administer: Intravenous, oral b.
Metabolized 3. Drug
interaction: Allopurinol 4. Toxicity:
Bone marrow depression 5. Use:
Immunosuppression |
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IV.
PYRIMADINE ANTAGONIST A.
5‑FLUOROURACIL (Fluorouracil) 1.
Action a.
Inhibit thymidylate synthetase after conversion to nucleotide, FdUMP b.
Cell cycle specific 2.
Disposition a.
Administer intravenously b.
Hepatic metabolism 3.
Toxicity a.
Bone marrow depression ‑ nadir 1‑2 weeks b.
GI toxicity 4.
Use a.
Breast CA b.
Colon CA B.
CYTOSINE ARABINOSIDE (Cytosar‑U) 1.
Action a.
Inhibits DNA synthesis b.
Competitively inhibits DNA polymerase c.
S phase specific 2.
Disposition a.
Administer: Intravenous, intrathecal b.
Hepatic metabolism 3.
Toxicity a.
Bone marrow depression b.
GI 4.
Use: ALL ‑ children HORMONAL
THERAPY I.
SEX HORMONE A.
Introduction 1.
Exact pharmacologic mechanism unknown 2.
Modify growth of hormone dependent tumors 3.
Lack cytotoxicity 4.
Offer little curative potential 5.
Eventual resistance common 6.
Tolerable side effects B.
Estrogens: Diethylstilbestrol (DES) 1.
Use a.
Advanced prostatic cancer b.
Post menopausal breast cancer 2.
Disposition a.
Administration: oral 3.
Side Effects a.
Gynecomastia b.
Sodium and fluid retention c.
Acute hypercalcemia C.
Progestins: Medroxyprogesterone (Provera, Depo‑Provera) 1.
Use: Endometrial cancer 2.
Disposition a.
Administer: Im or p.o. b.
metabolized in liver 3.
Side effects a.
Mild fluid retention b.
Liver function abnormalities |
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D.
Androgens: Nandrolone
(Durabolin), Methandrostenolone (Dianobol)
Methyltestosterone (Oreton) 1.
Use: Breast cancer 2.
Action
a. Mechanism of antitumor effect unknown
b. Stimulate bone marrow production of red blood cells
c. Anabolic effect 3.
Disposition: Administer IM and P.O.
4. Side effects
a. Virilization
b. Fluid retention
c. Abnormal liver function ‑ methandrostenolone,
methyltestosterone II.
Antihormonal Agent A.
Antiestrogen: TAMOXIFEN (Nolvadex) 1. Action a.
Competitively blocks the access of natural hormones to specific cell
membrane receptors b. Limited to endocrine derived tumors 2.
Use: Breast cancer 3.
Side effects
a. Menopause‑like reaction: hot flashes, nausea
b. Increasing bone pain ‑ may require drug discontinuation B.
Antiadrenal: MITOTANE (Lysodren) 1.
Action: Selective cytotoxicity on normal and cancerous adrenal
tissues 2.
Use: Breast cancer, adrenal cancer 3.
Toxicities
a. GI
b. Dermatologic
c. Acute total adrenal insufficiency III.
CORTICOSTEROIDS: Hydrocortisone, Prednisone, Dexamethasone 1.
Action
a. Lysis of mature lymphocytes ‑ cytotoxic
b. Decrease cellular energy caused by impairment of glucose
transport
c. Suppress mitosis in dividing lymphocytes
d. Protein catabolic effect
e. Sodium and water retention
f. Enhance gastric secretion
g. Bone marrow suppression 2.
Use
a. ALL, CLL
b. Hodgkin's and non‑Hodgkin's Lymphoma
c. Myeloma
d. Breast cancer 3.
Complications
a. Cushingoid state: Sodium and fluid retention
b. Hypertension
c. Diabetes
d. Osteoporosis
e. Immunosuppression
f. Peptic ulcer
g. Psychosis |
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PLANT
ALKALOIDS |
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I.
VINCRISTINE (Oncovin), VINBLASTINE (Velban) 1.
Action a.
Produce metaphase arrest b.
Dissolution of microtubule protein c.
May also inhibit nucleic acid and protein synthesis d.
M phase specific 2.
Use a.
Vincristine: ALL, lymphosarcoma, Hodgkin's b.
Vinblastine: Hodgkin's, choriocarcinoma, breast cancer c.
There is no cross resistance between the two drugs 3.
Toxicity a.
Vincristine: Neurologic ‑ numbness and tingling of extremities, weakness, loss of
reflexes b.
Vinblastine: Bone marrow depression 4.
Disposition a.
Administer intravenously b.
Bile excretion |
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IMMUNOADJUVANT |
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I. BACILLUS
CALMETT‑GUERIN (BCG vaccine)
1. Action
a. Broad spectrum recall immune response to a variety of antigens
b. Local inflammatory effect |
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c.
BCG ‑ Tumor cross reactivity d.
Enhancement of phagocytosis activity of macrophages e.
Stimulation of lymphocytosis f.
Enhancement of a humoral antibody‑tumor cytotoxic reaction 2.
Clinical significance a.
Only significant when there is relatively low tumor cell burden b.
Therefore rational to use only after reduction of tumor bulk by
radiation, surgery, or chemotherapy c.
Considered experimentaly 3.
Disposition
a. Local application to tumor
b. Intravenous II.
Immunorestorative Agent: LEVAMISOLE 1.
Action a.
Restore depressed immunity toward normal b.
Effective only if given discontinuously 2.
Clinical significance a.
Still only considered experimental b.
Earlier enthusiasm has lessened INTERFERON 1.
Action
a. Endogenous antiviral agent b. Theory:
Cancer is caused by viral agent in immunoincompetent individuals c.
Exogenous interferon should cure viral infections d.
May cure cancer e.
Currently under clinical trials
LAETRILE I.
Discussion 1.
Controversial drug with no proven effect 2.
Never proven under controlled double blind studies 3.
Currently undergoing clinical trials
TOXICITIES I.
Introduction 1.
Have narrow therapeutic indices 2. Acute
toxicities in rapidly dividing normal tissues ‑ bone marrow, GI
tract, hair follicles II.
Nausea/Vomiting
Nitrogen Mustard, Mithramycin, Cis‑Platinum, Nitrosoureas
‑ more than 80% incidence 2. Onset:
Within minutes 3. Duration:
Up to 12‑24 hours 4. Treatment a.
Phenothiazine administered 30‑60 minutes before chemotherapy b.
Marijuana: clinical trials |
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III.
Alopecia 1.
Severe: Doxorubicin, Nitrosoureas, Cyclophosphamide 2.
Common: Alkylators, Antimetabolites, Antibiotics, Alkaloids 3.
Onset: 1‑2 weeks 4.
Reversible
5. Prevention
a. Tourniquet left in place 5‑10 minutes after IV push
b. Thermal cooling IV. Local
Effects 1.
Extravasation of vesicant drugs causes pain, necrosis, and
sloughing of tissues 2. Drugs:
Daunomycin, Doxorubicin, Nitrogen mustard, Streptozotocin,
Thiotepa, Vinblastine, Vincristine 3.
Treatment
a. Prevention
b. 1/6 M sodium thiosulfate for extravasations of Nitrogen
Mustard
c. Ice packs directly on area for 30‑60 minutes
‑lower metabolic activity and mitotic activity (?) d.
Hot moist soaks and normal saline (?) e.
Hydrocortisone 50‑100 mg. (?) f.
Debridement of necrotic tissue ‑ Doxorubicin ADMINISTRATION I.
Avoid 1.
Veins near joints ‑ cannot observe extravasation 2.
Veins previously irradiated 3. Veins with
poor venous circulation II. Procedure 1.
Select large vein on dorsum of hand or forearm 2.
Insert 21‑23 gauge scalp‑vein needle (Butterfly) 3.
Inject 2‑3 ml. of normal saline and observe for
extravasation 4.
Inject drug 1 ml at a time and draw back observing for good blood
return 5.
Flush line with 5 ml. normal saline after infusion COMBINATION
CHEMOTHERAPY I.
Effectiveness 1.
Selective drugs work at different phases of cell cycle 2.
Drugs that have different toxicities 3.
Superior to single drug in many diseases 4.
Less resistance |