Anticancer Drugs Ref Book :Dr SK Srivastava,Dr H L Sharma and Dr KK sharma,Dr K D Tripathi,

1. Anticancer Drugs ?
Dr.lokendra Sharma
Professor of Pharmacology

2. Treatment options of cancer:?
• No Treatment: Before 1940
• Surgery: before 1955
• Radiotherapy: 1955~1965
• Chemotherapy: after 1965
• Immunotherapy and Gene therapy

3. Cell Cycle ?
Cell Cycle Specific Agents
• Antimetabolites
• Bleomycin
• Podophyllin Alkaloids
• Plant Alkaloids
Cell Cycle Non-Specific
Agents
• Alkylating Agents
• Antibiotics
•Cisplatin
• Nitrosoureas

4. Chemotherapy
Cell cycle effects of anticancer drugs ?
CCS
Drugs
CCS Drugs CCNS Drugs
G1 - S Etoposide Platinum compounds
S Antimetabolites Alkylating agents
G2 – M Bleomycin
Etoposide
(Ref Harrison
17th
/525)
Anthracyclines
Dactinomycin
M Vinca alkaloids
Taxanes
Ixabepilone
Estramustine
Mitomycin
Camptothecins

5. Goals of Therapy ?
Cure or induce prolonged ‘remission’
Macroscopic and microscopic features of
the cancer disappear
 Acute Lymphoblastic Leukaemia
 Wilm`s tumor, Ewing`s sarcoma etc.
 In children, Hodgekin`s lymphoma, testicular
teratoma and choriocarcinoma

6. Goals of Therapy Palliation:
?
 Shrinkage of evident tumour,
 Alleviation symptoms ,prolongation of life
 Breast cancer, ovarian cancer, endometrial
carcinoma,
 CLL, CML,
 Small cell cancer of lung and Non-Hodgekin
lymphoma

7. Goals of Therapy ? Insensitive
 less sensitive but life may be prolonged
 Cancer esophagus, cancer stomach,
 sq. cell carcinoma of lung,
 melanoma,
 pancreatic cancer,
 myeloma,
 colorectal cancer

8. Aim of Therapy : Adjuvant therapy
For mopping up of residual cancer cells including
metastases after Surgery,
Radiation and immunotherapy etc.
Routinely used now
Mainly in solid tumours

9. General Principles
 Analogous with Bacterial chemotherapy –
differences are
 Selectivity > drugs > limited
 No or less defence mechanism – Cytokines
adjuvant now
 All malignant cells > killed >stop progemy
 Subpopulation cells differ in rate of
proliferation and susceptibility to
chemotherapy

10. General Principles
 Drug regimens or combined cycle
therapy after radiation or surgery
 Complete remission should be the goal
 Formerly single drug – now 2-5 drugs
in intermittent pulses
 Total tumour cell kill – COMBINATION
CHEMOTHERAPY

11. COMBINATION CHEMOTHERAPY
SYNERGISTIC ?
Drugs which are effective when used alone
Different mechanism of action
Differing toxicities
Different mechanism of toxicities
Synergistic biochemical interactions
Optimal schedule by trial and error method
More importantly on cell cycle specificity

12. Classification ?

According to chemical structure and sources of drugs
– Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts,
Hormones and Others

According to biochemistry mechanisms of anticancer action:
– Block nucleic acid biosynthesis
– Direct influence the structure and function of DNA
– Interfere transcription and block RNA synthesis
– Interfere protein synthesis and function
– Influence hormone homeostasis

According to the cycle or phase specificity of the drug:
– Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents
(CCSA)

13. Some Alkylating Agents used in cancer Chemotherapy
Agent Route of
Admin.
Cancer where preferred Delayed Toxicity
1. Busulphan Oral CML, PV BMD, bleeding, skin
pigmentation adrenal
insufficiency, pulmonary
fibrosis
2. chlorambucil Oral CLL, PV BMD, bleeding
3. Cyclophosphamid Oral, i.v All, NHL, PV, Carcinoid
tumour, Neurobalstoma
BMD, bleeding,
hemorrhagic, cystitis
4. Melphalan Oral Multiple myeloma BMD, Bleeding
5. Mechlorethamine i.v. Hodgkin’s disease BMD, alopecia, Diarrhea
oral ulcer leukaemia
6. Cisplatin i.v. CA tests, ovary, cervix, lung,
head & neck, thyroid,
Melanoma
Renal damage, ototoxicity,
neuropathy, BMD
7. Dacarbazine i.v. Melanoma, Hodgkin’s disease BMD
8. Carmustine
(BCNU)
i.v. Brain tumors Leucopenia,
thrombocytopenia
9. Lomustine
(CCNU)
Oral Brain tumors Leucopenia,
thrombocytopenia
10. Thiotepa i.v. CA bladder (early) & Ovary BMD

14. Some antimetabolites used in cancer chemotherapy
Agent Route
of
admin.
Cancer (s) where
preferred
Delayed toxicity
Cytarabine i.v. AML BMD, nausea,
Vomiting stomatitis
ataxia (cerebrallar)
5- Fluorouracil i.v. Carcinoma head &
neck, Stomach colon,
breast
BMD, Oral and GI
ulceration, nausea,
diarrhea, neurotoxicity,
*hand and foot
syndrome
6-
Mercaptopuine
Oral All BMD, Hyperuricaemia,
immunosuppression,
hepatotoxicity
Methotrexate Oral All, choriocarcinoma,
osteogenic sarcoma
BMD, vomiting, oral &
GI ulcers hepatotoxicity
(acute & chronic)
Thioguanine Oral AML BMD, Hyperuricaemia

15. Block nucleic acid (DNA, RNA) biosynthesis
Antimetabolites:
• Folic Acid Antagonist: inhibit dihydrofolate reductase
(methotrexate)
• Pyrimidine Antagonist: inhibit thymidylate synthetase
(fluorouracil) ; inhibit DNA polymerase (cytarabine)
• Purine Antagonist: inhibit interconversion of purine
nucleotide (6-mercaptopurine and 6-Thioguanine)
• Ribonucleoside Diphosphate Reductase Antagonist:
(hydroxyurea)

16. Structure & Function of DNA
 Alkylating Agent:
Mechlorethamine, cyclophosphamide, ifosfamide,
chlorambucil, Mephalan, Busulfan, Nitrosoureas and
Thio-TEPA
 Platinum:
Cis-platinium, carboplatin and imatinib
 Antibiotic:
Bleomycin and mitomycin C
 Topoismerase inhibitor: camptothecin analogues
and podophyllotoxin and antibiotics like actinomycin
D, daunorubicin and doxorubicin

17. Sites of Antineoplastic Action ?
PALA = N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.

18. Clinical Considerations ?
 Early intensive start …. helpful
 Complete remission….. goal
 Combined chemotherapy useful
…..delayed emergence of resistance
 Combined chemotherapy …..curative
 Treatment must continue past the time
when cancer cells can be detected
using conventional techniques

19. Resistance ?
 Intrinsic:
malignant melanoma, renal cell cancer, and brain
cancer, exhibit primary resistance
 Acquired:
Single drug:
change in the genetic apparatus amplification or increased
expression of one or more specific genes
Multidrug resistance:
Resistance variety of drugs exposure to a single variety of drug
increased expression of a normal gene (the MDR1 gene) for a cell
surface glycoprotein (P-glycoprotein) involved in drug efflux

20. Toxicities ?
Harmful to normal tissues too
Steep dose response curve
Low therapeutic index
Particularly harmful to rapidly multiplying
normal tissues: GI mucosa, Bone Marrow, RE
system and gonads and hair cells
Effects are in dose dependent manner

21. Toxicities ?
 Bone marrow depression – limits treatment
 Buccal mucosa erosion – high epithelial turnover
(stomatitis, bleeding gums)
 GIT: Diarrhoea, shedding of mucosa, haemorrhage
Nausea, vomiting – CTZ direct stimulation
 Skin: alopecia
 Gonads: oligospermia, impotence, amenorrhoea and
infertility
 Lymphoreticular system: Lymphocytopenia and inhibition
of lymphocyte function – loss of host defense mechanism –
susceptibility to infections
 Carcinogenicity
 Teratogenicity and Hyperuricemia

22. Distinctive Toxicities of Alkylating Agents ?
Drug Toxicity
Cyclophosphamide Alopecia, Hemorrhage cystitis, SIADH
Ifosfamide Hemorrhagic cystitis, SIADH
Busulfan Pulmonary fibrosis, Hyper pigmentation,
Adrenal insufficiency
Procarbazine Secondary leukemias, Disulfiram like
reaction, behavioral changes, CNS
depression
Cisplatin Emesis, Nephrotoxicity, Peripheral
sensory neuropathy, ototoxicity

23. Countering the Toxicities ?
 Intermittent therapy
 Folinic acid rescue
 Systemic Mesna (sodium-2-mercaptoethane
sulfonate) administration and irrigation by
acetylcysteine – detoxify toxic metabolites
 Ondansetron
 Hyperurecaemia: uricosuric agents like allopurinol
 Platelet and granulocyte transfusion
 Granulocyte colony stimulating factors (GM-CSF/G-
CSF) – recovery of garnulocytopenia

24. Drugs used to prevent toxicity of Anti cancer drugs
Drug Mechanism Indications
Allopurinol Inhibit xanthine oxidase Prevent hyperuricemia from tumor
lysis syndrome
Rasburicase Recombinant urate oxidase Prevent hyperuricemia from lysis
Mesna Neutralizing agent Prevent hemorrhagic cystitis due to
ifosfamide and high dose
cyclophosphamide
Leucovoring Replete Tetrahydrofolic acid Rescue after high dose methotrexate
Amifostine Prevent radiation induced
xerostomia and
Prevent radiation induced
xerostomia and cisplatin induced
nephrotoxicity
Dexrazoxane Iron chelator Prevent cardiotoxicity due to
anthracyclines
Palifermin Keratinocyte growth factor Prevent mucositis following
chemotherapy
Pilocarpine Cholinergic agonist Radiation induced xerostomia
Pamidronate and
Zolendronate
Bisphosphonates Hypercalcemia of malignancy

25. Drugs used to prevent toxicity of
Anti cancer drugs
Drug Mechanism Indications
Epoetin alpha
and darbopoetin
alpha
Erythropoietin Anemia
Filgrastim, peg-
filgrastim
G-CSF and Febrile neutropenia prophylaxis
Sargramostim GM - CHF
Oprelvekin IL-11 Thrombocytopenia
Ondansetron 5-HT3 antagonist Nausea and vomiting
Granisetron
Palonosetron
Aprepitant NK – 1 antagonist Cisplatin induced delayed vomiting

26. Interfere Protein Synthesis
 Antitubulin:
vinca alkaloids (vincristine and vinblastin) and
taxanes (paclitaxel and docetaxel)
Bind tubulin, destroy spindle to produce mitotic
arrest
 Influence amino acid supply:
L-asparaginase
.

27. Tyrosine Kinase Inhibitors
Drug Inhibit TK activated Indication
Axitinib VEGFR – 1,2,3 Advanced renal cell carcinoma
Bosutinib Abl –bcr, src CML
Crizotinib c-MET, ALK Non small cell lung carcinoma
Cabozantinib c-MET, VEGFR-2 Medullary carcinoma thyroid
Dasatinib abl -bcr CML
Erlotinib EGFR Non small cell lung carcinoma
Pancreatic carcinoma
Geftinib abl-bcr, c- KIT, PDGF Non small cell lung carcinoma
Imatinib her-2/neu, erb-B2 CML GIST
Lapatinib abl-bcr Breast carcinoma
Nilotinib VEGFR-1,2,3 PDGFR α β
c-KIT
CML
Pazopanib abl-bcr Advanced renal cell carcinoma

28. Tyrosine Kinase Inhibitors
Drug Inhibit TK activated Indication
Regorafenib VDGFR2, TIE2 Colorectal carcinoma GIST
Ruxolitinib JAK 1,2 Myelofibrosis
Sorafenib VEGFR, PDGFR RAF Renal cell carcinoma
Hepatocellular carcinoma
Sunitinib VEGFR, PDGFR c- KIT, FLT-3 RET Renal cell carcinoma,
Pancreatic neuroendocrine
tumors GIST
Tofacitinib JAK Rheumatoid arthritis
Vandetanib VEGFR, EGFR Medullary carcinoma
thyroid
Vemurafenib BRAF Maliganant melaonma

30. Monoclonal Antibodies
S.
No.
Monoclonal antibody Targeted
against
Indication Comments
1 Rituximab CD - 20 Non hodgkin lymphoma
2 Alemtuzumab CD - 52 Low grade lymphomas and
CLL
3 Trastuzumab HER 2/neu Breast Carcinoma Can cause
cardiotoxicity
4 Cetuximab and
panitumumab
EGFR EGFR – positive metastatic
colorectal carcinoma
Cause rash,
Hypomagnesemia and
tnterstitial lung
disease
5 Bevacizumab VEGF Metastatic colorectal
carcinoma
Combined with 5 - FU
6 Gemtuzumab CD-33 CD-33 Positive AML Linked to
calicheamicin
7 I131
– Tositumomab
Y90
– Ibritumomab
tiuxetan
CD-20 Relapsed lymphomas Conjugated with
radioisotopes
8 Denileukin diftitox - Recurrentcutaneous T-cell
lymphoma
Recombinant IL – 2
plus diphtheria toxin

31. Therapy of choice for various cancers
S. No. Diagnosis Treatment of choice
1 ALL Induction: Vincristine + Prednisolone+Daunorubicin+
Asparaginase+Intrathecal Methotrexate
Consolidation: Hyper-CVAD alternated with
cytarabine+Methotrexate
2 AML Cytarabine+Daunorubicin/Idarubicin
3 CML Imatinib
4 CLL FCR or Fludarabine
5 Hairy cell leukemia Cladribine
6 Hodgkin disease ABVD
7 Non hodgkin
lymphoma
CHOP-R
8 Multiple Myeloma Bortezomib+Dexamethasone+Lenalidomide
9 Waldenstrom
macroglobulinemia
FCR(Fludarabine,Cyclophosphamide,Rituximab)
10 Polycthemia vera Hydroxyurea

32. Therapy of choice for various cancers
S. No. Diagnosis Treatment of choice
11 Non small cell lung
cancer
Cisplatin + Vinorelbine ± Bevacizumab
12 Small cell lung
cancer
Cisplatin + Etoposide
13 Mesothelioma Cisplatin + Pemetrexed
14 Head and neck cancer Cisplatin + 5-FU

33. Cancer Chemotherapy
Agent Cancer (s) where preferred Delayed toxicity
Antibiotics
1. Bleomycin Carcinoma testis, malignant
effusion (intracavity)
Alopecia, oedema of hand,
pulomonary fibrosis, stomatitis
2. Dactinomycin Wilm’s tumour Alopecia, BMD, Stomatitis, Oral
ulcer
3. Daunorubicin AML Alopecia, BMD, Cardiomyopathy
4. Doxorubicin HL, NHL, neuroblastoma,
Carcinoma thyroid, stomach,
carcinoid tumouir, sarcomas,
osteogenic sarcoma
Alopecia, BMD, Cardiomyopathy,
stomatitis
5. Mitomycin Carcinoma stomach Thrombocytopaenia, leukopaenia
6. Streptozotocin
(sreptozocin)
Insulinoma Renal damage, hypoglycaemia,
hyperglycaemia, liver damage,
BMD, fever eosinophilia,
nephrogenic diabetes insipidus

34. Some natural products in cancer chemotherapy
Agent Cancer (s) where
preferred
Delayed toxicity
Plant Alkaloids
1. Docetaxel Advance case of
carcinoma breast
Neurotoxicity, fluid retention,
neutropaenia
2. Etoposide Carcinoma testis,
choriocarcinoma
Alopecia, BMD
3. Paclitaxel Carcinoma breast, ovary BMD, peripheral neuritis
4. Vinblastine HD Alopecia, BMD, Loss of reflex
5. Vincristine ALL, NHL Alopecia, BMD, Peripheral
neuritis
6. Vinorelbine Carcinoma lung BMD, fatigue, constipation,
hyporeflexia paresthesia

35. Miscellaneous agents including monoclonal antibodies in cancer chemotherapy
Agent Route of admin. Cancer(s) where used Delayed toxicity
1. Asparaginase i.v. ALL in child Hepatotoxicity, mental
depression,
pancreatitis
2. Cisplatin i.v. CA testis, ovary,
cervix, lung, head &
neck, thyroid,
melanoma
Renal damage,
otoxicity neuropathy,
BMD
3. Hydroxyurea Oral CML, AML (blast
crisis)
BMD
4. Mitotane Oral Adrenocortical
carcinoma
Adrenal insufficiency,
diarrhea, lethargy, skin
rash (transient)
5. Mitoxantrone Oral AML BMD, cardiotoxicity,
alopecia
6. Imatinib Oral CML (chronic phase)
& blast crisis
Fluid retention
(periorbital and ankle
oedema), diarrhoea,
myalgia
7. Trastuzumab i.v. Carcinoma breast
(metaastatic)
BMD,
cardiomyopathy,
pulm. Toxicity,
cardiac failure

36. Hormones, their antagonists and related agents in
cancer chemotherapy
Agent Route of admin Cancer(s) where
preferred
Delayed toxicity
Corticosteroids
Hydrocortisone
Prednisone
Oral
Oral
All, CLL, NHL, HL
Multiple myeloma
Fluid retention,
Hypertension, diabetes
mellitus, susceptibility
to infection, moon
face
Androgens
Testosterone
i.m. Premenopausal breast
cancer (oestrogen
receptor positive)
Fluid retention
masculinization
Oestrogens
Diethylstilboesterol
Ethinyloestradiol
Oral
Oral
Carcinoma prostate,
Postmenopausal breast
cancer (oestrogen
receptors negative)
Feminization, Fluid
retention
Progestins
Hydroxyprogesterone
Medroxyprogesterone
i.m.
Oral
Carcinoma
endometrium
None

37. Influence hormone homeostasis
Estrogens and estrogen antagonistic drug (EE,
SERM-tamoxifene)
Androgens and androgen antagonistic drug
(flutamide and bicalutamide)
Progestogen drug (hydroxyprogesterone)
Glucocorticoid drug (prednisolone and others)
Gonadotropin-releasing hormone inhibitor:
nafarelin, triptorelin
aromatase inhibitor: Letrozole and
anastrazole

38. Hormones, their antagonists and related agents in
cancer chemotherapy
Agent Route of admin Cancer(s) where
preferred
Delayed toxicity
Antiandrogen
Flutamide
Oral Carcinoma prostate None
Antiandrogen
Tamoxifen
Oral Carcinoma breast
(early stage, metastatic
after surgery)
None
Others GnRH Agonist
Goserelin
Leuprolide
s.c)
s.c.)
Carcinoma prostate None
Aromatase Inibitors
Aminogulutethimide
Oral Metastatic breast
cancer
None
Peptide hormone
Inhibitor
s.c. Carcinoid tumour None

39. Choice of drug in some malignancies where the response of chemotherapy is very
good
Cancer Treatment of choice
1. Acute lymphocytic leukaemia Induction: Vincristine + presnisone
Maintenance: Methotrexate + Mercaptopurine +
Cyclophosphamide
2. Hodgkin’s disease stage I and II
Stage III and IV
Radiotherapy
Doxorubicin +
bleomycin+vinblastine+dacarbazine
3. Non Hodgkin’s disease Cyclophosphamide + doxorubicin + vincristine +
prednisolone
4. Choriocarcinoma Methotrexate + folic acid or cisplatin + etoposide
5. Cancer testis Bleomycin + cisplatin+ etoposide
6. Wilm’s tumour Surgery + radiotherapy followed by vincristine +
dactinomycin

40. Choice of drug in some malignancies where the
response of chemotherapy is good
Cancer Treatment of choice
1. Acute myeloid leukaemia Cytarabine + idarubicin/daunorubicin
2. Chronic lymphocytic
leukaemia
Chlorambucil + prednisone (if indicated) +
fludarabine or cytarabine alone or in combination
with other drugs
3. Chronic myelogenous
leukaemia
Busulfan or interferon, imatinib (bone marrow
transplatation in selected patients)
4. Multiple myeloma Melphalan + prednisone
5. * Carcinoma breast stage 1 Tomoxifen after breast surgery
6. Endometrial carcinoma Progestins or tamoxifen
7. Carcinoma cervix Radiation + cisplatin (localized),
cisplatin/carboplatin (metastatic)
8. Carcinoma prostate GnRh agonist or oestrogen + androgen anatagonist
(flutamide)

41. Choice of drug in some malignancies where the
response of chemotherapy is average
Cancer Treatment of choice
1. Carcinoma breast stage II to
IV
Cyclophosphamide + methotrexate + 5-FU or
Transtuzumab + prednisone + antioestrogen
2. Carcinoma ovary Cisplatin or carboplatin + paclitaxel + interferom
3. Carcinoma thyroid Radioidine (I131
), doxorubicin, cisplatin
4. Carcinoma stomach 5-FU + doxorubicin + mitomycin
5. Carcinoma colon 5-FU + leucovorin + irinotecan
6. Osteogenic sarcoma Doxorubicin or methotrexate with leucovorin after
surgery
7. Melanoma Dacarbazine, cisplatin, interferon

42. Choice of drug in some malignancies where the
response of chemotherapy in unsatisfactory
Cancer Treatment of choice
1. Carcinoma lung Etopise + cisplatin, vinorelbine
2. Carcinoma head and
neck
5-fu+cisplatin or cisplatin + paclitaxel
3. Carcinoma adrenal
gland
Mitotane
4. Carcinoid tumour Doxorubicin + cyclophospamide or 5-
FU + octreotide
5. Polycythaemia vera Busulfan, chlorambucil or
cyclophospamide

44. Alkylating Agents
Mechanism of Action:
• Nitrogen mustards inhibit cell reproduction binding
irreversibly nucleic acids (DNA)
• After alkylation, DNA is unable to replicate
• no synthesize proteins and essential cell metabolites
• Consequently, cell reproduction inhibited cell eventually dies
inability maintain metabolic functions.

45. Alkylating Agents(CCNS)

46. Subgroups of Alkylating Agents
• 1) Nitrogen mustards
• 2) Nitrosoureas
• 3) Alkyl sulfonates
• 4) 4-Platinum Coordination Compounds
1-Nitrogen Mustards
E.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucil
a-Mechlorethamine
- first alkylating agent employed clinically
- bifunctional, thus can crosslink DNA
- extremely unstable and is inactivated within a few minutes following administration.
Thus it is given IV.
Clinical Uses
-Hodgkin’s Disease
-Non-Hodgkin’s Lymphoma
Toxicity/ Side Effects
- Dose limiting toxicity is bone marrow depression

47. Nitrogen Mustards
• Mechlorethamine:
– Uses: IV
– MOPP (Mechlorethamine – oncovine-prednisolone and procarbazine)
in Hodgekin`s lymphoma and disease
– ADRs: Severe Vomiting, myelo and immunosuppression
– Extravasation – severe local toxicity
• Cycolphosphamide:
– Transformed active aldophosphamide and phospharamide
– orally
– Used Hodgkin's lymphoma, breast and ovary cancers
– Ifosphamide longer half life and used mainly testicular tumour

48. Nitrogen Mustards – contd.
• Chlorambucil: orally, active against lymphoid tissues
(Ch. Lymphatic leukaemia and non-Hodgkin's
lymphoma)
• Busulfan: orally, active against CML
• Carmustine: IV, effective against brain tumors and
Hodgkin's lymphoma
• Dacarbazine: Different from other alkylating agents –
action against RNA and protein synthesis
– Used Melanoma and Hodgkin's lymphoma

49. Antimetabolites
Folic acid Antagonists: MTX
Purine Antagonists: 6MP and 6TG
Pyrimidine Antagonists: 5FU and cytarabine
General Characteristics:
 Antimetabolites S phase-specific drugs structural analogues
of essential metabolites and that interfere with DNA
synthesis.
 Myelosuppression dose-limiting toxicity

50. Methotrexate – Folate Antagonist
• MOA:
– Structures MTX and folic acid similar
– MTX actively transported mammalian cells and inhibits
dihydrofolate reductase
– the enzyme that normally converts dietary folate to the
tetrahydrofolate form required for thymidine and purine
synthesis
• Leucovorin rescue:
– Administered as a plan in MTX therapy
– Leucovorin (Folinic acid) is directly converted to
tetrahydrofolic acid - production of DNA cellular protein
inspite of presence of MTX
– Used to rescue bone marrow and GIT mucosal cells

51. Methotrexate – contd.
• Kinetics:
– orally/IM /IV intrathecally , good oral absorption
– CSF entry - intrathecal
• Indications:
– Choriocarinoma - was the first demonstration of curative
chemotherapy
– Tumors of head and neck
– Breast cancer
– Acue lymphatic leukemia
– Meningeal metastases of a wide range of tumors

52. Purine Antagonists – 6MP, 6TG
6-Mercapapurine (6-MP) and others
• Exact mechanisms uncertain – inhibit purine base
synthesis
• Used in childhood Acute lymphatic Leukaemia for
maintenance and remission
• combination MTX choriocarcinoma
• Metabolized xanthine oxidase (inhibited by
allopurinol) and allopurinol dose has to be adjusted
to ½ or 1/4th
• Well tolerated, mild myelosuppression ,
hepatotoxicity on long term administration

53. Antimetabolites (Pyrimidine Antagonists) -
5 FU
• MOA:
– Fluorouracil analogue of thymine
– Converted to 5-fluoro-2deoxy-uridine
monophosphate (5-FdUMP)
– 5-FdUMP inhibits thymidylate synthase and blocks
conversion of deoxyuridilic acid to
deoxythymidylic acid – failure of DNA synthesis
• Indications: solid tumors, especially breast,
colorectal, and gastric tumors and squamous
cell tumors of the head and neck

54. Antibiotics
• Anthracyclines (doxorubicin and dau norubicin),
Dactinomycin, Bleomycin, and mitomycin
• Anthracyclines:
– Enters themselves into DNA and causes DNA break
– Activates TopoisomeraseII and cause break in DNA strands
– Generates excess free radicals causing production of
superoxide – damage to DNA
– Known to damage cardiac cells also (unique)
– Resistance developes due to increased eflux of drug
– Uses: Doxo- Breast, ovary, lung, [prostate and acute
lymphatic leukaemia
– Dauno- ALL and AML

55. 2-Nitrosoureas
• - bifunctional
• - active against broad spectrum of neoplastic disease
• - inhibits synthesis of both DNA and RNA, as well as proteins
• - These drugs are highly lipophilic, so they can easily cross blood-brain-barrier,
and are great for CNS tumors.
• - Big problem in this class is that they are highly mutagenic and highly
carcinogenic.
• - Major toxicity is DELAYED bone marrow depression & Pulmonary fibrosis.
Clinical uses
- primary and metastasis tumors of the brain
- Hodgkin’s Disease
- Non-Hodgkin’s lymphoma
- Adenocarcinoma of stomach, colon, and rectal cancer
- Hepatocarcinoma
E.G.:
a-Carmustine
b-Lomustine

56. 3-Alkyl Sulfonates
Busulfan
Clinical uses
Great effect on for Chronic granulocytic Leukemia
Toxicity/ Side Effects
- Dose limiting toxicity is bone marrow depression.
- Pulmonary infiltrates and pulmonary fibrosis
- Tonic-clonic seizures in epileptics

57. 4-Platinum Coordination Compounds
E.G.:
Cisplatin
• forms crosslinks within DNA strands.
Clinical Uses
- Very powerful against TESTICULAR CANCER
- Also good for carcinomas of ovary, bladder, head, and neck
Toxicity/ Side Effects
- Renal tubular damage (minimized via massive hydration coupled with anti-
emetics)
- Ototoxicity and peripheral neuropathy
- VERY SEVER vomiting( Ondanosetron…?)
Carboplatin:
is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.

58. 3-Etoposide
• podophyllotoxin, a toxin found in the mandrake
root.
• An inhibitor of the enzyme topoisomerase II.
cause breaks in the DNA inside the cancer cells
and prevent them from further dividing and
multiplying. Then the cells die.
Side effect
• Vomiting & alopecia
• Bone marrow suppression
uses
• It has been useful for treatment of testicular
cancer and small cell lung cancer.

59. thanks.