l14 Cancer Chemotherapy

7/30/2019 l14 Cancer Chemotherapy

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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.

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l14 Cancer Chemotherapy