Chemotherapy of Cancer: Submitted by Syama - J.S Roll No:15 2 SEM M Pharm Pharmacology
Chemotherapy of Cancer: Submitted by Syama - J.S Roll No:15 2 SEM M Pharm Pharmacology
Chemotherapy of Cancer: Submitted by Syama - J.S Roll No:15 2 SEM M Pharm Pharmacology
CANCER
SUBMITTED BY
SYAMA . J.S
ROLL NO :15
2ND SEM
M PHARM PHARMACOLOGY
CANCER WORLD CANCER DAY
FEBRUARY 04
o The medical term for tumor or cancer is Neoplasm, which means a relatively
autonomous growth or uncoordinated cell proliferation of body tissue.
o Excessive study of neoplasm and its development diagnosis and treatment is called
Oncology.
CHARACTERISTIC OF CANCER
Cancer arises as a result of a series of genetic and epigenetic changes, the main genetic
lesions being:
• inactivation of tumour suppressor genes
• the activation of oncogenes (mutation of the normal genes controlling cell division and
other processes).
Cancer cells have four characteristics that distinguish them from normal cells:
• uncontrolled proliferation
• loss of function because of lack of capacity to differentiate
• invasiveness
• the ability to metastasise.
Cancer cells have uncontrolled proliferation because of changes in:
• growth factors and/or their receptors
• intracellular signalling pathways, particularly those controlling the cell cycle and apoptosis
• telomerase expression
• tumour-related angiogenesis 4
NORMAL CELL VS CANCER CELL
NORMAL CELL CANCER CELL
Mortal (die ~ 50 division) Immortal (divide indefinitely)
Contact inhibition Loss of contact inhibition
Stay bound together Can easily detach from each other
Controlled cell death (Apoptosis) Unresponsive to apoptosis
Controlled cell division Increased rate of cell division
Control of angiogenesis Unregulated angiogenesis
Mature in to functional cells Do not mature in to functional cells
Nomenclature
On the basis of parenchymal cells they are derived
not all tumors are cancerous; tumours can be Benign and Malignant.
• Benign tumours
aren’t cancerous, They can often be removed and in most cases,
they do not come back, cells do not spread to other parts of the body
• Malignant tumours-
are cancerous , cells can invade nearby tissues and spread to other parts of the
body(Metastasis)
Beningn Malignant
2. Biological Agents-
a) Bacterial Agents: Peptic ulcers and chronic gastritis left untreated for a long time leads to
gastric cancer.
b)Fungal Agents: Aspergillus flavus releases aflatoxins in stored food and grains
contaminated food is consumed (especially by Hepatitis B virus infected patients) it
leads to Heptocellular carcinoma.
c) Viral Agents: Human pappilloma virus-Cervical cancer
Epstein- barr virus-Nasopharyngeal carcinoma
Kaposi’s sarcoma herpes virus – Kaposi’s sarcoma
Hepatitis B & C virus – Hepato cellular carcinoma
Human T- cell leukemia virus – T cell leukemia
3. Chemical Agents
Alkylating agents, Acylating agents, Polyaromatic Hydrocarbons, Aniline dyes , Arsenic,
Anthracenes , Acetyl imidazole , dimethyl carbamyl chloride ,Benzene
Tobacco smoke , nicotine
Alcohol-Liver and digestive tract cancer
Coaltar
INTRINSIC FACTORS
• In other cases one/more base may be added or deleted and sometimes large segments of DNA
molecule are accidently repeated , deleted or moved
• Damaged genes are implicated in the development of cancer and are called ONCOGENES.
Oncogene are gene, whose presence in certain form and or overactivity can stimulate the
development of cancer.
• They contribute to the development of cancer by instructing cells to make protein that
stimulate excessive cell growth and division
• Types of genes
1. The growth promoting genes
1.By change in the structure of the gene . This result in the synthesis of an abnormal gene product
(oncoprotein) which has an abnormal function.
the amplification of DNA sequences in proto oncogene can lead to over expression
Oncogenes arise from the mutation of proto oncogene , they resemble oncogenes in that they
code for the production of protein involved in growth control
• Oncogene code for an altered version of these growth control protein oncogene cause a cell
growth – signaling pathway became hyperactive.
If a pair of tumor suppressor genes are either lost from a cell or inactivated through mutation,
their functional absence might allow cancer to develop.
TSG are family of normal genes that instruct cells to produce protein that restrain cell growth
and division.
The loss of such protein allows cells to grow and divide in an uncontrolled fashion
One particular tumor suppressor gene code for aprotein called P53 that can trigger cell suicide
(apoptosis)
The normal function is to correct errors that arise when cells duplicate their DNA prior to cel
division.
Eg . People with xeroderma pigmentoscem have an inherited defect in DNA Repair gene.
• Cancer may begin because of the accumulation of mutation involving oncogene, TSG and
DNA repair gene
e.g colon cancer begin with a defect in TSG that allow excessive cell proliferation. The
proliferating cells acquire additional mutation involving DNA repair gene and other TSG, and
many other related gene – finally leads malignant metastatic cancer
• Mutation also seen in the genes that activate and deactivate carcinogens and in those that
govern the cell cycle, cell senescence, cell suicide (apoptosis), cell signaling and cell
differentiation.
DIAGNOSIS OF CANCER
• Traditional chemotherapeutic agents act by killing cells that divide rapidly, a critical
property of most cancer cells.
1.General toxicity
a) Bone marrow suppression(myelosuppression):
Leukopenia ,agranulocytes,thrombocytopenia and aplastic anaemia. Infection and
bleeding is common.
reduced by –platlet transfusion
Granulocyte Colony stimulating factor(G-CSF)
Erythropoietin
Bone marrow transplantation
Using bone marrpw-sparing drugs L-asparginase,bleomycin,
cisplatin,vincristine
b) Immunosuppression
Decreased lymphocytes ,patients are prone for oppurtunistic diseases with
fungi, bacteria,viruses,parasites etc
C) GIT
Nausea and vomiting(stimulation of CTZ)
Cisplatin -emetogenic potential(antiemetics 5-HT3 antagonists- Ondansteron)
Stomatitis, Diarrhoea,GI bleeding,shedding of mucosa,Ulcers in gut mucosa
Drugs causing Mucositis- Bleomycin ,Actinomycin D, daunorubicin
,doxorubicin
d) Skin and Hair
Alopecia (loss of hair) due to damage of hair follicles,reversible on stoppage of
therapy. Dermatitis and skin rashes
e) Gonads
oligozoospermia and infertility in males, Amenrrohea and infertility in females
f) Foetus
During pregnancy-Abortion ,Foetal death, teratogenesis
g) Carcinogenicity
Secondary malignancy
Development of leukaemia in patients with prolonged use of alkylating agent
h) Hyperuricaemia
Gout and urate stones in UT due to excessive cell destruction
Prevention: good hydration, allopurinol and corticosteroids
i) Mutagenicity
ANTICANCER DRUG CLASSIFICATION
1.Depending upon the MOA on the cell level
2 . CELL CYCLE SPECIFIC AND NON –SPECIFIC GRUGS
G1 phase (presynthetic phase)-Synthesis of enzymes and other cellular components needed for DNA synthesis
S phase (Synthetic phase):DNA synthesis takes place
G2 phase(premitotic phase)-Synthesis of cellular components for mitosis(proteins and RNA synthesis
M phase-Mitotic cell division takes place
G0 phase (resting phase)-Cells stop dividing temporarily or permanently
CELL CYCLE NON SPECIFIC CELL CYCLE SPECIFIC
Aldophosphamide
Adverse effects
Haemorrhagic cystitis associated with dysuria and haematuria due to irritation of
bladder mucosa by acrolein
Mesna binds it and inactivates acrolein
Alopecia
Hepatic damage
Nausea and vomiting
2. Melphalan
Very effective in MULTIPLE MYELOMA ,Ovarian carcinoma, Breast cancer
Less irritant locally , less alopecia ,rarely renal or hepatic dysfunction
Nausea and vomiting less frequent
ADR
Bone marrow Depression (Myelosuppression)
Infections , diarrhoea and pancreatitis
3.Mechlorathamine(mustine)
First nitrogen mustard
Highly reactive and local vesicant
Use
Hematological cancers , lymphomas , solid tumors
Hodgkins as part of MOPP, CML, CLL
Adverse Effects
Anorexia,
nausea,
vomiting
Bone marrow depression, aplasia
Menstrual irregularities
4. Ifosfamide
Congener of cyclophosphamide
Longer half life than cyclophosphamide
Less alopecia and less emetogenic than cyclophosphamide
USE
Bronchogenic, Breast ,Testicular, bladder, head and neck carcinoma, Oesteogenic
sarcoma and some lymphoma, Used for germ cell testicular tumors
• ADR
Can cause hemorrhagic cystitis and severe neurological toxicity ,lethargy ,
confusion
5 ) CHLORAMBUCIL
Slowest acting and least toxic alkylating agent
Main action on lymphoid series produces marked lympholytic action
USE
Drug of choice for long term maintenance therapy of CLL (Chronic Myeloid
Leukaemia)
Non Hodgkins lymphoma
Immunosuppressant property
ADR
Pulmonary fibrosis, Hepatotoxicity, dermatotoxicity, Myelo suppression
• Miscellaneous alkylating agent- Thiotepa , Ethyleneimines and methylmelamins.
THIO-TEPA
Triethylene phosphoramide
High toxicity
USE
Rhabdomyosarcoma, breast cancer, Ovarian cancer
ADR
Infertility, Myelosuppression
• Platinum Coordination compounds – Cisplatin Cl NH3
CISPLATIN
• Non cell cycle specific killing Pt
Cl NH3
Methotrexate
DNA
• Pharmacological actions
• Cytotoxic actions
Predominant on bone marrow
Ulceration of intestinal mucosa
Crosses placenta interferes with embroyogenesis foetal malformations and
death
• Immunosupressive action
Prevents clonal expansion of B & T lymphocytes
• Anti-Inflammatory action
Interferes with release of inflammatory cytokines IL-2, IL-6,IL-8 & TNFalpha
↓ Rheumatoid Factor production
• Uses of methotrexate
• Antineoplastic
Choriocarcinoma and tropoblast tumor
Remission of ALL in children
Carcinoma on breast, head & neck, bladder, ovarian cancer
• Immuno-supressive agent
Rheumatoid arthritis, resistant asthma
Crohns disease, wegeners granulomatosis
Prevention of graft versus host reaction
• Psoriasis
• Medical termination of pregnancy
• Non –Hodgin lymphoma
Adverse effects
• Megaloblastic anemia
•Thrombocytopenia, leukopenia, aplasia
• Oral, intestinal ulcer , diarrhoea
• Alopecia , liver damage, nephrpathy
Treatment of methotrexate toxicity
Folinic acid (citrovorum factor, N5 Formyl THF)
IM/IV 8 to 24 hrs after initiation of methotrexate
120 mg in divided doses in first 24 hrs, then 25 mg oral/IM 6 hrly for next 48 hrs
• Mechanism of Resistance
Impaired transport of methotrexate into cells
Production of altered forms of DHFR that have decreased affinity for the inhibitor
Increased concentration of intracellular DHFR through gene amplification or altered
gene regulation
Decreased ability to synthesize methotrexate polyglutamates
Increased drug efflux
• PURINE ANTAGONISTS : 6- mercaptopurine , 6 Thioguanine(6TG)
MERCAPTOPURINE
6-Mercaptopurine is an analogue of purine and is highly effective anticancer drug
Acts in S phase of cell
MOA
The drug is converted in the cells to ribonucleotide of 6-mercaptopurine,which then suppresses
the denovo biosynthesis of purines and hence of DNA.
• Use: Acute Lymphoblasticleukemia (ALL)
Choriocarcinoma, Used in solid tumour
ADR
– Bone marrow & GIT mainly
Hepatic necrosis rarely
– Hyperuricaemia
PYRAMIDINE ANTAGONISTS- 5-FU ( fluorouracil),Cytarabine
USES USES
Metastatic Ovarian and Breast carcinoma
Head and Neck cancer Ovarian Cancer
Small cell Lung cancer Breast canncer
Esophageal adenocarcinoma Small cell cancer lung,pancreatic,gastric and
Urinary and hormone refractory Prostate cancer head , neck carcinoma
AIDS related kaposi,s sarcoma Neutropenia
ADR Arrhythmias
Anaphylactoid reaction because of solvent Fall in BP
cremophor
Reversible myelosuppression( Granulocytopenia)
Stocking and glove neuropathy
Nausea
Chest pain
Arthalgia
Myalgia
ANTICANCER ANTIBIOTICS-Actinomycin D ,Doxorubucin
,Bleomycin,Mitomycin ,Daunorubicin ,Epirubucin
ACTINOMYCIN D
• Actinomycin D is very potent antineoplastic antibiotic obtained from the species of
STREPTOMYCES.
MECHANISM OF ACTION
The drug intercalates into the minor groove of double helix between guanine-
cytosine base pairs of DNA and interfere with the movement of RNA polymerase
along the gene and thus preventing transcription.
It may also cause strand breaks and stabilize DNAtopoisomerase II complex
. CLINICAL USES
It is used in the combination with surgery and vincristine for the treatment of wilm’s
tumour and soft tissue sarcomas.
• ADVERSE EFFECT
• Vomiting
• Stomatitis
• Diarrhoea
• Bone marrow depression.
• It can damage the skin that is exposed to radiation
2. DACTINOMYCIN
Uses:
• Wilms tumor,
• gestational choriocarcinoma
• Adverse effects
• bone marrow supression
• Irritant like meclorethamine
• sensitizes to radiation, and inflammation at sites of prior radiation therapy may
occur
• Gastrointestinal adverse effects
• ENZYMES- L-asparaginase
Isolated from E.coli Use: Acute Lymphocytic Leukemia (ALL)
Adverse Effect• Hepatic damage
• Hypersensitivity , hemorrhage
• Hyperglycemia, headache, hallucinations , confusion, coma
• HYDROXY UREA
Ribonucleoside diphosphate
reductase Adverse Effects: Myleosuppression
Ribonucleotides - Deoxyribonucleotides Hypersensitivity