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CANCER CHEMOTHERAPY
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CANCER(neoplastic disease): disease
characterized by uncontrolled cell division,
invasion and metastasis.
Multiple factors may be involved :
*sex, age, race, genetic predisposition;
*environmental factors: radiation, chemical
carcinogens,( those in tobacco smoke), viruses ( HBV, HCV, HIV,
EBV) etc.
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Cancer treatment modalities:
- surgery, radiotherapy, chemotherapy;
CHEMOTHERAPY:
1) Primary induction therapy- primarytreatment in advanced cancers with no otheralternative;
2) Neoadjuvant chemotherapyin localized
disease in situations when surgery/RT/bothcannot be used;
3) Adjuvant chemotherapy-to RT / surgey/both.
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-The anticancer drugs:
-either kill cancer cells or modify their growth.
- most act on the proliferating population of
cells.
-they act against metabolic sites essential forcancer cell replication
- these drugs do not specifically recognize
cancer cells and affect all proliferating cells bothnormal and abnormal cells (they are one of the
most toxic drugs used in therapy).
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A schematic summary of cell cycle
kinetics is presented in next figure:
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Anticancer drugs may be:
*CELL CYCLE SPECIFIC DRUGS (CCS):
They act specifically on cells undergoing cycling:
Antimetabolites, Bleomycin, Vinca alkaloids
*CELLCYCLE NONSPECIFIC (CCNS) DRUGS:
They act in both cycling and resting states
(alkylating agents, some antibiotics).
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The role of drug combinations: - it provides maximal cell kill;
-it provides a broader range of interactionsbetween drugs and and tumour cells;
-it may prevent /slow development of
resistance.Principles in selecting drugs in the most
effective combination: *efficacy; * mechanism of
interactions
*toxicity; * avoidance of arbitrary
*optimum scheduling; dose changes
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Eg. of drugs combinations:
ACRONYMS:
ABVD: doxorubicin(
adriamycin)+bleomycin+vinblastine+dacarbazine
MOPP : mechlorethamine+
vincristine+procarbazine+prednisone
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GENERAL TOXICITY OF CYTOTOXIC
DRUGS
Tissues with rapidly multiplying cells are
affected in a dose dependent manner by
majority of drugs.
* Bone marrow: -depression with
granulocytopenia, agranulocytosis,
thrombocytopenia, aplastic
anemiainfections and bleedings are theusual complications.
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Lymphoreticular tissue : lymphocytopenia and
inhibition of lymphocyte function suppression of
cell mediated and humoral immunity.The mostimportant are the opportunistic infections with
Candida , viruses ( herpes zoster, cytomegalovirus),
pneumocystis carinii, toxoplasma gondii.
Gastrointestinal tract: stomatitis, diarrhoea,haemorrhages , nausea, vomiting( due to the
stimulation of the chemoreceptor trigger zone and
generation of emetic impulses from the upper
gastrointestinal tract);
Skin :alopecia due to damage to the cells in hair
follicles; dermatitis.
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Gonads:inhibition of gonadal cells witholigozospermia, inhibition of ovulation,amenorrhoea.
Foetus:cytotoxic drugs in pregnant woman:abortion, foetal death, teratogenesis.
Carcinogenicity:secondary cancers( appear with
greater frequency many years after the use ofcytotoxic drugs).
Hyperuricaemia:gout, urate stones.
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Classification of anticancer drugs
(according to the mechanism of action)
1)Antimetabolites ;
2)Alkylating agents;
3)Antibiotics;
4)Vinca alkaloids;5)Taxanes;
6)Epipodophyllotoxin;
7)Camptothecin analogues;
8)Miscellaneous;
9) Hormones and antihormones.
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1)ANTIMETABOLITES
They are structurally similar to normal DNAcomponents and they generally inhibit synthesis ofnormal purine / pyrimidines or folic acid or competewith them in DNA or RNA synthesis.
They act especially in S phase.
a)Folic acid antagonists
b)Purine antagonists
c)Pyrimidine antagonists
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a)Folic acid antagonistsMethotrexate : inhibition of dihydrofolate reductase
decreased DNA synthesis and cell death. It also affects RNA
synthesis and protein synthesis
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-orally or i.v.
*acute leukemias in childrens in maintainingremission ;
*choriocarcinoma,
*breast cancer, head, neck, bladder cancerlung carcinoma and in high doses inosteogenic sarcomas.
*immunosuppressant.
-Major toxicity: on bone marrow.!The toxic effects on normal cells may be
reduced by administration ofFolinic acid(Leucovorin).
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b)Purine antagonists Mercaptopurine (6MP) ) a structural analog
of hypoxanthine
Thioguanine (6TG) a structural analog of
guanine
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Mercaptopurine (6MP) )
* a structural analog of hypoxanthine
* It is converted to nucleotide form inhibitseveral enzymes involved in purine metabolism,with inhibition ofpurine ring.
Clinical uses: *the maintenance of the remission ofchildhood acute leukemia; myelogenousleukemia,granulocytic leukemia.
Side effects: *bone marrow depression.
*Hyperuricaemia, hepatotoxicity;*6MP causes more nausea and
vomiting than 6-TG
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Thioguanine (6TG) a structural analog ofguanine
Clinical uses: in acute myelogenous leukemia(+cytarabine and
daunorubicin)
Acute lymphoblastic leukemia.
Side effects:
* bone marrow depression.
*Hyperuricaemia
In acute leukemia, both have been used incombination regimens to induce remission and 6-MP to maintain it.
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c)Pyrimidine antagonists
Fluorouracil (5-FU) -a pyrimidine analog
It is converted in the body to the
corresponding nucleotide which inhibits
thymidylate synthetase critical for the
synthesis of thymine nucleotides inhibition
of DNA synthesis.
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Clinical uses: orally, i.v. and topically.
* slowly growing solid tumors (breast, ovarian,
pancreatic, colorectal,urinary, liver), i.v.
* skin cancers topically (premalignant keratoses,
cutaneous basal cell carcinomas).
Side effects:
* bone marrow depression, severe ulceration of
the oral and GI mucosa, neurotoxicity.
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Cytarabine
*i.v.,in acute myelogenous leukemia(in
combination)
*Hodgkins disease and non Hodgkin lymphoma.
* bone marrow depression
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2)ALKYLATING AGENTS
1.Nitrogen mustards:
mechloretammine,cyclophosphamide,
chlorambucil, melphalan
2.Nitrosoureas: carmustine, lomustine,
semustine
3.Alkyl sulfones: Busulfan
4. Triazenes: Dacarbazine
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They exert their cytotoxic effects by covalently binding to
various cellular constituents. The major reaction is alkylation of
N7 (nitrogen position 7) of guanine within DNA.
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1.Nitrogen mustards
Mechlorethamine*Hodgkins disease as a part of MOPP
regimen(vincristine, procarbazine, prednisone)
and non Hlymphomas.It is given i.v.
*It causes severe bone marrow depression,
nausea, vomiting.
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CyclophosphamideIt is inactive as such and must be activated tocytotoxic forms (aldophosphamide, phosphoramide
mustard and acrolein) in the liver by microsomalenzymes.
Clinical uses:
* ovarian and breast cancers, H disease, lung cancer;
it is used orally or i.v., alone or as a part of a regimen.*as immunosuppressant
Side effects:
-hemorrhagic cystitis (caused by chemical irritation of
the bladder mucosa by acrolein);-alopecia, nausea, vomiting, diarrhea;
-prolonged treatment can produce interstitialpulmonary fibrosis and cardiomyopathy.
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Chlorambucil:
It is a very slow acting alkylating agent
*the drug of choice for long term maintenance
therapy for chronic lymphatic leukemia (incombination with prednisone). It is administeredorally.
Melphalan
* multiple myeloma, breast, ovarian cancer ;
* Bone marrow depression
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2.Nitrosoureas: carmustine, lomustine,
semustine
They are highly lipid soluble and cross the
blood brain barrier making them useful in
malignancies of the CNS (meningeal leukemia
and brain tumors).
They cause delayed bone marrow
depression(it takes nearly 6 weeks to
develop).
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3.Alkyl sulfones: Busulfan
It is the drug of choice for chronic myeloid
leukemia. It is given orally.Side effects: -endocrine dysfunction(adrenalinsufficiency);pulmonary fibrosis is a specificsideeffect;skinpigmentation;myelosuppression
;hyperuricaemia.4. Triazenes: Dacarbazine
They have primary inhibitory action on RNA andprotein synthesis.It is activated in the liver.
Its most important indication is malignantmelanoma. It is administered i.v.
It causes marked nausea, vomiting,myelosuppression.
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ANTIBIOTICS
*Dactinomycin (Actinomycin D)
*Antracyclines : Doxorubicine ,Daunorubicine
Mitoxantrone
*Bleomycin
*Plicamycin
*Mitomycin C
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*Dactinomycin (Actinomycin D)
-Wilms tumour, rhabdomyosarcoma, Ewings
sarcoma, soft tissues sarcomas, Kaposis
sarcomas, i.v. (with surgery and Vincristine)
(+/- RT)
-as immunosuppressive agent
- The major side effect: bone marrow
depression.
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*Antracyclines
-Doxorubicine: Hodgkins (H) disease ( ABVDregimen), solid tumors (of the breast,ovary,endometrium, testicle , stomach, liver ,
lung) and acute leukemia;i.v.It causes irreversibledose-dependent cardiotoxicity.
-Daunorubicine- used in acute myeloid leukemias;it causes bone marrow depression, GI
disturbances, alopecia.-Mitoxantrone-analogue of doxorubicine , used in
prosatate cancer
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*Bleomycin
-testicular carcinoma(+Cisplatin and Vinblastine)
- H disease and nonH lymphomas and
carcinomas of the head, neck, skin,
genitourinary tract;
- It has mucocutaneous toxicity and causes
pulmonary fibrosis
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*Plicamycin:
-embryonal testicular cancer, disseminated cancers
-highly toxic drug
*Mitomycin C
-resistant cancers of stomach, colon, cervix, rectum,
bladder.
-It causes bone marrow and gastrointestinal toxicity.
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VINCA ROSEA ALKALOIDS:
VINBLASTINE AND VINCRISTINE
Vincristine(i.v. route):- derived from the periwinkle plant Vinca
Rosea.
Clinical uses:
-childhood acute lymphoblastic leukemia,
-H disease and nonH lymphomas(MOPP regimen), s
-solid tumors in children and tumors of the breast, lung in adults.
Adverse effects: peripheral neuropathy, alopecia, GI
disturbances, autonomic nervous system dysfunctions.Vinblastine( i.v.) : used in metastatic testicular carcinoma( in
combination) and H disease; it causes bone marrow depression
( leucopenia)
Vinorelbine : lung, ovarian,breast cancers.
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Mechanism of action:
inhibit tubulin polymerization which disrupts
assembly of microtubules an important part ofthe cytoskeleton and the mitotic spindle
mitotic arrest in metaphasecell death.
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TAXANES
Mechanism of action:
They function as mitotic
spindle poisons : they
bind to microtubules with
enhancement of tubulin
polimerization finally
inhibition of mitosis andcell division.
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Paclitaxel
- by i.v. infusion
-metastatic ovarian and breast carcinoma after failure offirst line chemotherapy and relapse cases;
-advanced cases of head,neck cancer, small cell lungcancer, esophageal carcinoma.
- It causes myelosuppression, neuropathy.
Docetaxel-It is a more potent congener of paclitaxel-same clinical uses
- It causes neutropenia
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EPIPODOPHYLLOTOXINS
ETOPOSIDE and TENIPOSIDE are semisynthetic glycosidesof the activepodophyllotoxin extracted from the mandrakeplant.
Mechanism of action: at low c% they block cells at the S-G2interface ; at high c% they cause G
2
arrest; they stimulateDNA topoisomerase II to cleave DNA.
Etoposide : used in lung, prostate, testicular carcinomas
( orally and i.v.).
It causes GI irritation, bone marrow depression(dose limiting
leucopenia), alopecia; Teniposide resistant acute lymphoblastic leukemia.
It causes bone marrow depression (leucopenia), alopecia,gastrointestinal disturbances.
CAMPTOTHECIN ANALOGUES
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CAMPTOTHECIN ANALOGUESTopotecan and Irinotecan: semisynthetic analogues of
camptothecin, an antitumour principle obtained
from a Chinese tree.
They inhibit the activity of topoizomerase I , the key
enzyme responsible for cutting and religating single
DNA strandsDNA damage. Topotecan- metastatic carcinoma of ovary and small
cell lung cancer after primary chemotherapy has
failed. The major toxicity is bone marrow depression
(specially neutropenia).
Irinotecan prodrug decarboxylated in the liver to
the active metabolite ;used in metastatic / advanced
colorectal carcinoma, lung/cervix/ovary cancers etc.
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MISCELLANEOUS
L-ASPARAGINASE- from E. coli
- degrades L-asparagine to L-aspartic acid,depriving cancer cells of an essential metabolite
and may cause cell deathClinical uses: childhood lymphoblastic leukemia
Side effects:-liver damage, -pancreatitis,-CNSsymptoms,-allergic reactions (being a foreign
protein).
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CISPLATINis an inorganic platinum complex.
Mechanism of action :-similar to that of alkylatingagents.
Clinical uses: testicular tumors - alone/incombination,ovarian carcinoma, bladder
carcinoma.
Side effects: renal dose dependent dysfunction;
nausea,vomiting;acoustic nerve dysfunction.
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CARBOPLATIN- chemically related to cisplatin
-it is used alone in persistent or recurrent
ovarian carcinoma (i.v.)
-it causes dose- dependent marrow depression
(thrombocytopenia)
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PROCARBAZINE : inactive as such
After metabolic activation it depolymerizes DNAand causes chromosomal damage. Inhibitionof nucleic acid synthesis also occur.
It is a component of MOPP regimen for
Hodgkins disease non Hodgkin lymphomasand oat cell carcinoma of lung. It is givenorally.
Side effects:vomiting, leucopenia,thrombocytopenia, dermatitis.
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HORMONES and ANTIHORMONES
1.SEX HORMONES
They are used in hormone dependent cancers to
change the hormonal balance.
-androgens:testosterone propionate:in advancedbreast cancer with metastasis;
-antiandrogens: -Flutamide: antagonizes androgen
action on prostate carcinoma and has palliative
effect in advanced or metastatic cases.
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-estrogens: -diethylstilbestrol/ ethynylestradiol:
carcinoma prostate;
-antiestrogens:Tamoxifen- it is effective in breast
cancer in both pre as well as postmenopausalwomen; also effective in carcinoma of
endometrium
-progestins: hydroxyprogesterone: someadvanced,recurrent (after surgery or radiotherapy) and
metastatic endometrial carcinoma
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2. ADRENAL CORTICOSTEROIDSParticularly the glucocorticoid analogues
(hydrocortisone, prednisone)have been usefulin acute childhood leukemia, lymphomas, andother hematological cancers and in advancedbreast cancer.
3 . GOSERELIN ACETATE ; LEUPROLIDEThey are synthetic peptide analogues of naturally
GR hormones.
They inhibit the release of follicle stimulating
hormone(FSH) and luteinizing hormone (LH), withreduced testicular androgen synthesis.They areused in metastatic prostate carcinoma.