Anti Cancer drugs- Classification and general toxicities and general mechanism of action

1. Anticancer drugs Part I
Dr. Netravathi
Associate Professor
J. N. Medical College
Belagavi

2.  Introduction
 Treatment modalities
of cancer
 Choice & basic
principles of
chemotherapy
LEARNING OBJECTIVES
 General toxicity of
anticancer drugs
 Drugs used in
chemotherapy
 Toxicity amelioration

3. 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

5. 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

6. Modalities of
treatment

7. 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

8. ANTICANCER DRUGS
1. Cure or prolonged remission-
 Chemotherapy is the primary treatment
modality thatcan achieve cure or prolonged
remission in:
Acute leukemias Choriocarcinoma
Wilm’s tumour Hodgkin’s disease
Ewing’s sarcoma Lymphosarcoma
Retinoblastoma Burkitt’s lymphoma
Rhabdomyosarcoma Testicular teratomas,
Seminoma
Mycosis fungoides
C
h
i
l
d
r
e
n

9. 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

10. 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

11. 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)

12. 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.

14. Anticancer drugs

18. General Toxicity of Anticancer Drugs
 Results in
granulocytopenia,
agranulocytosis,
thrombocytopenia,
aplastic anaemia.
 Most serious toxicity
and often dose limiting
 Infections and
bleeding are the usual
complications.
BMS
 Cisplatin
 Vincristine
 Bleomycin
Bone
marrow

19.  Lymphocytopenia and
inhibition of lymphocyte
function  Suppressed
immunity
 Susceptibility to all infections
is increased
 E.g : Candida and others
causing deep mycosis ;
Herpes zoster,
 cytomegalovirus ;
Pneumocystis jiroveci ;
Toxoplasma
40
Lympho
reticular
tissue

20.  Stomatitis as an early
manifestation of
toxicity
 oral infections
 Bleeding gums
 Xerostomia leading to
dental caries
 Damage to cells of
hair follicles 
Alopecia
 Dermatitis
Oral
cavity
Skin

21.  Decrease in the rate
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
GIT
CINV

22.  Inhibition of gonadal
cells
oligozoospermia and
impotence in males
 Inhibition of ovulation
and amenorrhoea
 Mutagenesis in germ
cells
 abortion, foetal death
or teratogenesis.
Foetus
Gonads

23.  Secondary cancers 
leukaemias, lymphomas
and histocytic tumours
are more frequent
 Secondary to massive
cell destruction
 Acute renal failure,
gout and urate stones
in the urinary tract
may develop
Hyper
uricae
mia
Carcin
ogenic
ity

24. Toxicity
amelioration
Protectants
Drugs which reduces
the harmful effects of
chemotherapy &
radiotherapy
General
Measures
Protectants
• Colony stimulating factors
• Thiophosphate cytoprotectants
• Acrolein congener
• Iron chelator
• Thrombopoietic growth factors
• others

25. Colony Stimulating
Factors
Filgrastim, Molgramostim, Sarmograstim
Thiophosphate
cytoprotectants –
Amifostine
 Before Cisplatin to ↓ neuro/nephrotoxicity
 Before RT to head & neck ↓ xerostomia
Acrolein Conjugator Mesna  With cyclophosphamide/Ifosphamide
to prevent haemorrhagic cystitis
Iron chelator Dexrazoxane  Co-administered with
Doxorubicin to ↓ cardiomyopathy
Thrombopoietic growth
factors
Thrombopoietin  ↓ thrombocytopenia with
Carboplatin & Cyclophosphamide
Protectants

26. 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
(Leucovorin)
To rescue patients with BM suppression
with Mtx therapy
Bisphosphonates i.v for hypercalcemia due to malignancy
Protectants

27. 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

28. 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

29. Mechanism of action
Alkylation of guanine results in-
1. Mispairing : G≡T pairing
2. Opening of Imidazole ring
Excision of damaged Guanine
3. Cross – linking
4. Nucleic acid – Protein linkings
Bifunctional alkylating
agents
Alkylate a 2nd Guanine residue

30. Clinical pharmacology of individual drugs –
Nitrogen mustards
Mechlorethamine
 First nitrogen mustard , highly reactive and local
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

31. Cyclophosphamid
e
 ADR - Hemorrhagic cystitis(due to
acrolein) , cardiac dysfunction, pulmonary
toxicity and SIADH
Cyclophosphamide
4-OH Cyclophosphamide Aldophosphamide
Inactive Metabolities
Phosphoramide
Mustard
Anti-tumor effects
Acrolein
Hemorrhagic
cystitis
NORMAL CELLS
TUMOUR CELLS

32. Ifosfamide
 Congener of cyclophosphamide
 longer t1/2
 utility in bronchogenic, breast,
testicular, bladder, head and neck
carcinomas
 produces greater neurotoxicity –and
haemorrhagic cystis than other
alkylating agents.
 less alopecia and is less emetogenic
than cyclophosphamide
Chlorambucil
 Very slow acting
 Active on lymphoid tissue
 Spares myelocytes
 Orally well tolerated
 Drug of choice for long-term
maintenance therapy for CLL

33. 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

34. Dacarbazine (DTIC)
 Primary inhibitory action on RNA and protein
synthesis
 used in combination regimens for Hodgkin’s
disease and in malignant melanoma
Temozolamide  Drug of choice for glioma and other
malignant brain tumours
Nitrosureas
 Carmustine, Lomustine, Semustine, Streptozocin
 Highly lipid soluble
 Cross blood brain barrier
 meningeal leukaemias and brain cancer
 Delayed neutropenia, visceral fibrosis, renal damage
Triazines

35. Thank you