Anticancer drugs Part I

Dr. Netravathi
Associate Professor
J. N. Medical College
Belagavi
LEARNING OBJECTIVES

 Introduction  General toxicity of

anticancer drugs
 Treatment modalities
of cancer  Drugs used in
chemotherapy
 Choice & basic
principles of  Toxicity amelioration
chemotherapy
 INTRODUCTION

 Neoplasia  abnormal mass of tissue ; growth is

uncoordinated and exceeds normal tissue

 Tumours  benign & malignant

 Cancer  common cause of death

 Latin word ‘ Karakinos’ = Crab

General approach to cancer therapy

 Kill or remove the cancer cell – cytotoxic drugs, surgery, irradiation

or targeted cytotoxic agents (Ab linked toxins etc)
 Inactivate components of oncogene signaling pathway-
 Inhibitor of growth factor receptor. eg. Receptor tyrosine kinase

 Antisense oligonucleotides

 Restore function of tumour suppressor gene- gene therapy

 Employ tissue specific proliferation inhibitor- hormonal agonists &
antagonists.
 Inhibit tumour growth , invasion, metastasis – inhibitors of
angiogenesis & matrix metalloproteinase
 Enhance host immune response – cytokine based therapy
 Reverse drug resistance – inhibitors of multidrug transport
Modalities of
treatment
ANTICANCER DRUGS

 The anticancer drugs either kill cancer cells or modify

their growth.
 Treatment of malignant diseases with drugs is a
rather recent—started after 1940- nitrogen mustard
was used
 In malignant diseases, drugs are used with the aim of:

1. Cure or prolonged remission

2. Palliation
3. Adjuvant chemotherapy
ANTICANCER DRUGS
1. Cure or prolonged remission-
 Chemotherapy is the primary treatment
modality thatcan achieve cure or prolonged
remission in:

C
Acute leukemias Choriocarcinoma
h
Wilm’s tumour i Hodgkin’s disease
Ewing’s sarcoma l Lymphosarcoma
Retinoblastoma d Burkitt’s lymphoma
Rhabdomyosarcoma r Testicular teratomas,
e Seminoma
n
Mycosis fungoides
ANTICANCER DRUGS

2. Palliation-
Gratifying results are obtained (shrinkage of
evident tumour, alleviation of symptoms) and life
is prolonged by chemotherapy in:
 Breast cancer
 Chronic lymphatic
leukemia
 Ovarian carcinoma
 Chronic myeloid leukemia
 Endometrial carcinoma
 Non-Hodgkin lymphomas
 Myeloma
 Head and neck cancers
 Prostatic carcinoma
 Lung (small cell) cancer
ANTICANCER DRUGS

3. Adjuvant chemotherapy –

 Drugs are used to mop up any residual

malignant cells (micrometastases) after surgery
or radiotherapy.

 This is routinely employed now and may achieve

apparent cure, especially in early breast, lung
and colonic cancers
Choice of anti-cancer drugs:
 Dose should be as close as possible to the
Maximum Tolerated Individual Dose.

 Combined drugs should:

 Negate effects of resistance
 Have PK or PD synergism
 Not overlap in their toxicities

 Tissue selectivity
High proliferating tissues – cell cycle specific agents
Slow proliferating tissues – DNA damaging
agents(Alkylators)
CELL-CYCLE SPECIFICITY:

 Drugs that act specifically on phases of the cell

cycle are called cell-cycle specific (CCS) and
are more effective in tumors with high-growth
fraction (leukemias, lymphomas).

 Drugs that are cell-cycle nonspecific (many

bind to and damage DNA) can be used in
tumors with low-growth fraction, as well as
tumors with high growth fraction.
Anticancer drugs
 General Toxicity of Anticancer Drugs

 Results in
granulocytopenia,
agranulocytosis,
thrombocytopenia,
aplastic anaemia.
Bone
marrow
 Most serious toxicity
and often dose BMS
limiting
Cisplatin
Vincristine
Bleomycin

 Infections and
bleeding are the usual
  Lymphocytopenia and
inhibition of lymphocyte
function  Suppressed
immunity

Lympho  Susceptibility to all infections

reticular is increased
tissue

 E.g : Candida and others

causing deep mycosis ;
Herpes zoster,

 cytomegalovirus ;
Pneumocystis jiroveci ;
Toxoplasma

40
  Stomatitis as an early
manifestation of
toxicity
Oral
cavity  oral infections

 Bleeding gums

 Xerostomia leading to
dental caries

 Damage to cells of
Skin
hair follicles 
Alopecia

 Dermatitis
  Decrease in the rate
GIT of renewal of the GI
mucous lining 
Diarrhoea, shedding
of mucosa,
haemorrhages

 Nausea and
vomiting  CTZ
stimulation +
generation of emetic
impulses/mediators
from the upper g.i.t.
and other areas
CINV
  Inhibition of gonadal
cells
Gonads oligozoospermia and
impotence in males

 Inhibition of ovulation
and amenorrhoea

 Mutagenesis in germ
cells

 abortion, foetal death

Foetus or teratogenesis.
  Secondary cancers 
Carcin
ogenic
leukaemias, lymphomas
ity
and histocytic tumours
are more frequent

 Secondary to massive
cell destruction

 Acute renal failure,

Hyperu gout and urate stones
ricaemi
a
in the urinary tract
may develop
 General
Toxicity Measures
amelioration

Protectants
•Colony stimulating factors
•Thiophosphate cytoprotectants
•Acrolein congener
•Iron chelator
•Thrombopoietic growth factors
•others
 Protectants

Colony Stimulating Filgrastim, Molgramostim, Sarmograstim

Factors

Thiophosphate  Before Cisplatin to ↓ neuro/nephrotoxicity

cytoprotectants –  Before RT to head & neck ↓ xerostomia
Amifostine

Acrolein Conjugator Mesna  With cyclophosphamide/Ifosphamide

to prevent haemorrhagic cystitis

Iron chelator Dexrazoxane  Co-administered with

Doxorubicin to ↓ cardiomyopathy

Thrombopoietic growth Thrombopoietin  ↓ thrombocytopenia with

factors Carboplatin & Cyclophosphamide
 Protectants

Others Levamisole : Immunostimulant with

5FU
Allopurinol : For hyperuricemia due to
rapid destruction of bulky tumour mass
Rasburicase : Recombinant urate
oxidase, Metabolises uric acid to
allantoin

Ondansetron  Addition of Dexamethasone/

Aprepitant ↑ protection
Folinic acid To rescue patients with BM suppression
(Leucovorin) with Mtx therapy
Bisphosphonates i.v for hypercalcemia due to malignancy
 General Measures

Pulse therapy  2-3 weeks interval

 Normal cells recover
 Cancer cells recover slowly
Selective exposure  Intraarterial infusion to limb, head & neck
malignancies
 Intrapleural/ peritoneal injection
 Topical (skin, buccal mucosa, vagina)
 ↓ systemic toxicity

Use drug combinations  According to their phase specific character

 Drugs with different mechanism of action
 According to anticancer spectrum
 Use right doses
 Kill within tolerated toxicities
 ALKYLATING AGENTS
 Nitrogen mustards
 Mechlorethamine
 Cyclophosphamide, ifosamide
 Melphalan, chlorambucil.
 Ethyleneimines & methylmelamines
 Altretamine , thiotepa
 Methyl hydrazine derivatives
 Procarbizine
 Alkyl sulfonates
 Busulfan
 Nitrosourea
 Carmustine & streptozotocin
 Triazines
 Dacarbazine, temozolomide
 Mechanism of action

Alkylation of guanine results in-

1. Mispairing : G≡T pairing

2. Opening of Imidazole ring
Excision of damaged Guanine

Bifunctional alkylating
agents
Alkylate a 2nd Guanine residue

3. Cross – linking
4. Nucleic acid – Protein linkings
Clinical pharmacology of individual drugs –
Nitrogen mustards

 First nitrogen mustard , highly reactive and local

Mechlorethamine vesicant.
 Topical application on cutaneous T cell
lymphoma

Cyclophosphamide  Most commonly used alkylating agent

 Given by orally, i.v
 Inactive as such, transformation into active
metabolies (Aldophosphamide, Phosphoramide
mustard)occurs in liver.
 Prominent immunosuppressant property
 The clinical spectrum of activity is broad – NHL,
CLL, Breast, Ovary, Solid tumors
 Autoimmune - RA ,Wegener’s, Nephrotic
syndrome
  ADR - Hemorrhagic cystitis(due to
Cyclophosphamid acrolein) , cardiac dysfunction, pulmonary
e toxicity and SIADH

Cyclophosphamide

4-OH Cyclophosphamide Aldophosphamide

TUMOUR CELLS
NORMAL CELLS

Inactive Metabolities
Acrolein
Phosphoramide Hemorrhagic
cystitis
Mustard
Anti-tumor effects
  Congener of cyclophosphamide
 longer t1/2
 utility in bronchogenic, breast,
testicular, bladder, head and neck
carcinomas
Ifosfamide  produces greater neurotoxicity –and
haemorrhagic cystis than other
alkylating agents.
 less alopecia and is less emetogenic
than cyclophosphamide
 Very slow acting
 Active on lymphoid tissue
Chlorambucil  Spares myelocytes
 Orally well tolerated
 Drug of choice for long-term
maintenance therapy for CLL
 Melphalan  effective in ; DOC- multiple myeloma &
advanced ovarian cancers

Ethelynamines

Thio-TEPA  High toxicity & rarely used

Altretamine  Recurrent ovarian carcinoma for palliative
treatment
 Kidney dysfunction is dose limiting toxicity.

Alkylsulfonate

Busulfan  Highly specific for myeloid elements vs Chlorambucil

 2nd choice drug to imatinib for chronic phase of
CML
 Hyperuricaemia, pulmonary fibrosis,
hyperpigmentation, adrenal insufficiency
Nitrosureas
Carmustine, Lomustine, Semustine, Streptozocin
Highly lipid soluble
Cross blood brain barrier
meningeal leukaemias and brain cancer
Delayed neutropenia, visceral fibrosis, renal damage

Triazines

 Primary inhibitory action on RNA and protein

Dacarbazine (DTIC) synthesis
 used in combination regimens for Hodgkin’s
disease and in malignant melanoma
Temozolamide  Drug of choice for glioma and other
malignant brain tumours
Thank you