chemotherapy agents

1. CHEMOTHERAPEUTIC
AGENTS FROM
PERSPECTIVE OF
RADIATION ONCOLOGIST
Dr Prachi Upadhyay
Moderator- Dr. Pavan Kumar / Dr. Ayush Garg

2. CONTENTS
• History
• Classification of anticancer drug
• Mechanism of action
• Chemotherapy

3. HISTORY
• Chemotherapy began during the world war II
after the observation of autopsy of soldiers who
died due to the use of nitrogen mustard
• Aplasia of bone marrow
• Dissolution of lymphoid tissue
• Ulceration of the GIT
• Led to the use of these agents to treat Hodgkins
and non-Hodgkins lymphomas at Yale in 1943
• Luis Goodman and Alfred Gillmen
demonstrated it for the first time.

4. PAUL EHRLICH
1854 - 1915
• Father of Chemotherapy
• Salvarsan for Treatment of
Syphilis
• Nobel Prize 1908
• “Magic Bullet Concept

5. MODES OF CHEMOTHERAPY
• PRIMARY CHEMOTHERAPY - chemotherapy is used as the
sole anti-cancer treatment in a highly sensitive tumor types
Example – CHOP for Non-Hodgkins lymphoma
• ADJUVANT CHEMOTHERAPY – treatment is given after
surgery to “mop up” microscopic residual disease
Example – Adriamycin, cyclophosphamide for breast cancer
• NEOADJUVANT CHEMOTHERAPY – treatment is given before
surgery to shrink tumor and increase chance of successful
resection
Example – Adriamycin, ifosfamide for osteosarcoma
• CONCURRENT CHEMOTHERAPY – treatment is given
simultaneous to radiation to increase sensitivity of cancer cells
to radiation
Example – Cisplatin, 5-fluourouracil, mitomycin C

6. 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)

7. CELL CYCLE AND CLINICAL IMPORTANCE
• All cells—normal or neoplastic—
must traverse before and during
cell division
• Malignant cells spend time in
each phase - longest time at G1,
but may vary
• Many of the effective anticancer
drugs exert their action on cells
traversing the cell cycle - cell
cycle-specific (CCS) drugs
• Cell cycle-nonspecific (CCNS)
drugs - sterilize tumor cells
whether they are cycling or
resting in the G0 compartment
• CCNS drugs can kill both G0 and
cycling cells - CCS are more
effective on cycling cells

8. • Information on cell and population kinetics of cancer cells explains, in
part, the limited effectiveness of most available anticancer drugs
• Information is valuable in knowing - mode of action, indications, and
scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS)
drugs
• CCS – effective against hematologic malignancies and in solid tumors
with large growth fraction
• CCNS drugs – solid tumors with low growth fraction solid tumors
• CCS drugs are given after a course of CCNS

9. DRUGS BASED ON CELL CYCLE
• Nitrogen Mustards
• Cyclphosphamide
• chlorambucil
• carmustine dacarbazine
• busulfan
• L-asparginase, cisplatin,
procarbazine and actinomycin D
etc.
CCNS
• G1 – vinblastine
• S – Mtx, cytarabine, 6-thioguanine, 6-
MP, 5-FU, daunorubicin, doxorubicin
• G2 – Daunorubicin, bleomycin
• M – Vincristine, vinblastine, paclitaxel
etc.
CCS

12. CLASSIFICATION
1. ALKYLATING AGENTS
2. ANTIMETABOLITES
3. ANTITUMOR ANTIBODIES
4. MITOTIC SPINDLE AGENTS
5. TOPOISOMERASE INHIBITORS
6. TYROSINE KINASE INHIBITORS
7. MONOCLONAL ANTIBODIES
8. MISCELLANEOUS AGENTS
9. HORMONAL AGENTS
10. CYTOPROTECTIVE AGENTS

13. ALKYLATING AGENTS
• Are cell cycle non specific, i.e act on dividing
as well as resting cells.
• Alkylate nucleophilic groups on DNA bases
• Position 7 of guanine residues in DNA/RNA is
specially susceptible, but other molecular
sites are also involved.
• Leads to cross linking of bases, abnormal
base pairing and DNA strand breakage

14. CLASSIFIED
1. Nitrogen mustards- Cyclophosphamide, Chlorambucil,
Ifosfamide
2. Alkyl Sulfonate- Busulfan
3. Nitrosoureas- Carmustine, Lomustine
4. Triazine- Dacarbazine, Temozolomide
5. Ethylenime- Thio- TEPA

15. MECHANISM OF ACTION
Alkylating Agents
Form highly reactive carbonium ion
Transfer alkyl groups to nucleophilic sites on DNA bases
Results in
Cross linkage Abnormal base pairing DNA strand breakage
↓ cell proliferation
Alkylation also damages RNA and
proteins

16. CYCLOPHOSPHAMIDE
• Most commonly used alkylating agent a prodrug
Cyclophosphamide
Aldophosphamide
Phosphoramide
mustard
Acrolein
Cytotoxic effect
Hemorrhagic cystitis
Mesna

17. USES OF CYCLOPHOSPHAMIDE
• Neoplastic conditions
– Hodgkins and non hodgkins lymphoma
– ALL, CLL, Multiple myeloma
– Burkits lymphoma
– Neuroblastoma , retinoblastoma
– Ca breast , adenocarcinoma of ovaries
• Non neoplastic conditions
– Control of graft versus host reaction
– Rheumatoid arthritis
– Nephrotic syndrome

18. COMMON TOXICITIES
• Hematopoietic toxicity
• Gastrointestinal toxicity
• Gonadal toxicity
• Pulmonary toxicity
• Alopecia
• Teratogenicity
• Carcinogenesis
• Myleosuppression

19. ATYPICAL ALKYLATING ( PLATINUM
COMPOUNDS )
• Cell cycle non specific.
• Platinum compounds act by covalently binding to DNA with
preferentially binding to N7 position in guanine and adenine
.
• Form strong covalent bonds – DNA cross linking

20. COMMONLY USED PLATINUM COMPOUNDS
• CISPLATIN
• CARBOPLATIN
• OXALIPLATIN

21. CISPLATIN
• CDDP – Cis Di amine Dichloro platinum
• Alkylating agent
• Used in – in concurrent settings and
ca bladder, ca ovary ,ca oesophagus, ca testis ,
head and neck, ca lung , ca gall bladder ,ca cervix,
sarcomas , melanoma , mesothelioma
 Administration – iv infusion, substituted with 2.5 lits of iv fluids ,
inj mannitol , inj mgso4 , inj kcl
 Highly emetogenic – should be given good anti emetic cover

22.  Mechanism of action – it damages DNA , RNA and inhibits
cell division
• Side effects – nausea / vomiting , low blood counts , renal
toxicity , ototoxicity , low ca, Mg, k , peripheral
neuropathy, loss of appetite , metallic taste
sensation, hair loss, diarrhoea, fatigue,
oral ulcers ,malena , anaphylactic reactions

23. ANTIMETABOLITES
• These drugs act in the S phase of cell cycle
• Thus only dividing cells are responsive
• Folate antagonists
- Methotrexate
• Purine antagonists
- 6-Mercaptopurine
- 6-Azathioprine
- 6-Thioguanine
• Pyrimidine antagonists
- 5-Flurouracil
- Cytarabine

24. METHOTREXATE
Folic acid
Tetra hydro folic acid
Purine synthesis
-
DRUG CLASS: Antemetabolite
Folate antagonist
Dihydro folic acid
Dihydro folate reductase
DNA synthesis
Cell cycle specific: S phase
AICAR
TS

25. • INTERMITTENT IV ADMINISTRATION
• IT CAN ALSO BE GIVEN :
 IM
 ORALLY
 REGIONAL INTRA-ARTERIAL INFUSION
(INTO THE SUPERFICIAL TEMPORAL OR SUPERIOR THYROID
ARTERY)

26. Adverse effects
• Megaloblastic anemia
• Thrombocytopenia, leukopenia, aplasia
• Oral, intestinal ulcer , diarrhoea
•Alopecia , liver damage, nephrpathy
 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
Treatment of methotrexate toxicity

27. USES OF METHOTREXATE
• Antineoplastic
• Choriocarcinoma and tropoblast tumor15 -30 mg/day
orally for 5 days
• Remission of ALL in children 2.5 to 15 mg/day
• Ca 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

28. MERCAPTOPURINE:
PURINE ANTAGONIST
Mechanism of action:
Inhibits the formation of nucleotides from
adenine & guanine ( purine)
Highly effective antineoplastic drugs.
Common side effects:
 Bone marrow depression
 Nausea and vomiting
 Hyperurecemia
DOSE
Active Phase: 2.5 mg/Kg/day I.V.
Maintenance Phase: ½ Dose

29. 5-FLUOROURACIL :
PYRIMIDINE ANTAGONIST
• Mechanism of action:
Disrupts pyrimidine synthesis
Capecitabine is an oral pro-drug
• Route of administration:
 Intravenously
 Orally
 continuous iv infusion

30. • Even resting cells are affected (though rapidly
multiplying cells are more susceptible) –
particularly useful for many solid tumors.
• Side-effects:
 Myelosuppression
Hand and foot syndrome
 Mucosal ulceration/mucositis
 Nausea and vomiting
 Alopecia.

31. MITOTIC SPINDLE AGENTS
• M phase of cell cycle
• Bind to micro tubular proteins – inhibit micro tubular
assembly --- dissolution mitotic spindle structures .
• Vinka alkaloids.
• Taxanes

32. VINCA ALKALOIDS
(VINCRISTINE, VINEBLASTINE)
• Inhibits microtubule formation (mitotic inhibitor)
• Inhibits RNA synthesis by affecting DNA dependent
RNA polymerases.
• Cell cycle specific (M phase)

33. COMPARISON BETWEEN
Vincristine
• Marrow sparing effect
• Alopecia more
common
• Peripheral & autonomic
neuropathy & muscle
weakness (CNS)
• Constipation
• Uses: (Childhood
cancers)
• ALL , Hodgkins, lymphosarcoma, Wilms
tumor, Ewings sarcoma
Vinblastine
• Bone marrow
supression
• Less common
• Less common, temp.
mental depresssion
• Nausea, vomiting,
diarrhoea
• uses
• Hodgkins disease & other lymphomas ,
breast cancer, testicular cancer

34. TAXANES ( PACLITAXEL,DOCETXEL )
• Isolated from bark of yew tree (
taxus brevifolia )
• Microtubule-stabilizing agent
• Blocking of cell cycle at the G2 or
M phase by promoting
microtubule polymerization.- Non
functional microtubules
• Commonly used agents –
paclitaxel ,docetaxel

35. MECHANISM OF ACTION
Cell cycle arrested in G2 and M phase

36. TAXANES USED
• PACLITAXEL
• DOCETAXEL
• CABAZITAXEL
• ERIBULINE
• ESTRAMUSTINE
• IXABEPILONE

37. COMON TOXICITIES OF TAXANES
• NEUTROPENIA.
• HYPERSENSITIVITY.
• PERIPHERIAL NEUROPATHY.
• ALOPECIA.
• CARDIOTOXIC.
• MYLEOSUPRESSION.

38. ANTITUMOR ANTIBIOTICS
(ACTINOMYCIN, BLEOMYCIN)
Mechanism of action:
Intercalate between DNA strands and
interfere with its template function. Cell
cycle non specific
Side effects:
Vomiting, stomatitis, diarrhea
Desquamation of skin, alopecia
Bone marrow depression
Pulmonary fibrosis(esp bleomycin)

39. COMMON ANTI TUMOR ANTIBIOTICS
• ACTINOMYCIN D
• BLEOMYCIN
• MITOMYCIN C
• DAUNORUBICIN
• DOXORUBICIN
• EPIRUBICIN
• IDARUBICIN
• MITOXANTRONE

40. DOXORUBICIN & DAUNORUBUCIN

41. • Doxorubicin:
• Used in acute leukemias, malignant lymphoma and
many solid tumors, direct instillation in bladder cancer
• Daunorubicin:
• Use limited to ALL and granulocytic leukemias
• Toxicity:
• Both cause cardiotoxicity (cardiomyopathy)
• Marrow Depression, Alopecia

42. MECHANISM OF ANTHRACYCLINE
CARDIAC TOXICITY
• As well as intercalating into DNA, daunorubicin avidly binds mitochondrial
inner membrane of cardiac muscle
• Daunorubicin chelates iron, which catalyzes formation of the free radical
semiquinone
• Redox cycling transfers high energy electron to oxygen, generating oxygen
free radicals
• Produce lipid peroxidation damage to mitochondrial membranes

43. EPIPODOPHYLLOTOXINS
• Etoposide & tenoposide
• Semisynthetic derivatives of podophyllotoxins
podophyllum peltatum (plant glycoside)

44. TOPOISOMERASE I INHIBITOR
• Topoisomerase I inhibitor prevents the ligation of DNA
• Irinotecan and topotecan are commonly used drugs
• Topotecan is approved in ovarian cancer
• Irinotecan is approved in colorectal cancer

45. TOPOISOMERASE INHIBITOR II INHIBITOR
• Etoposide ( VP 16 ) – semisynthetic derivative of
podophyllotoxin
• Induces strand breaks in DNA
• Indicated in small and non small cell lung cancer ,germ
cell tumor.
• Myelosuppression is commonly seen drug toxicity.

46. ETOPOSIDE
• Act in S & G2 phase
• Inhibit topoisomerase II which results in breakage of DNA
strands & cell death
• Uses:
• Testicular tumors , squamous cell cancer of lungs

47. L-asparaginase

48. L-asparaginase
• Isolated from E.coli
• Use: Acute Lymphocytic Leukemia (ALL)
• Dose :
• 6000 to 10000U/kg IV daily for 3-4 weeks
• A/E:
• Hepatic damage
• Hypersensitivity , hemorrhage
• Hyperglycemia, headache, hallucinations ,
confusion, coma

49. Hydroxyurea
• Uses:
• CML, Polycythemia,
psoriasis
• Dose:
• 20-30 mg/kg /day
orally
Ribonucleotides Deoxyribonucleotides
Ribonucleoside diphosphate
reductase
Hydroxyurea
• Adverse effects
• Myelosuppression
(Minimal)
• Hypersensitivity
• Hyperglycemia
• Hypoalbuminemia

50. Targeted Therapies

51. TARGETED THERAPIES
• Monoclonal antibodies: proteins that trigger the
body’s pathways involved in cancer growth to fight
cancer more effectively.
• EGFR: family of receptors found on surface of normal
and cancer cells that bind with an epidermal growth
factor (EGF) causing cells to divide.
• Tyrosine Kinase Inhibitors: Part of the cell that signals
it to divide and multiply; enhances cell growth. Still
investigational

52. TYROSINE KINASE INHIBITORS
• A tyrosine kinase receptor is a
molecular structure or site on the
surface of a cell that binds with
substances such as hormones,
antigens, drugs, or
neurotransmitters

53. MECHANISM OF ACTION
When it binds with
one of the triggering
substances, the
receptor performs a
chemical reaction,
which in turn triggers
a series of reactions
inside the cell.

54. MONOCLONAL ANTIBIODIES
Mechanism Of Action

55. • Monoclonal antibodies such as Rituximab and
Trastuzumab are also use in the cancer
chemotherapy.
• This antibodies activate the host immune
mechanism and kills the cancer cells.
• Rituximab is used for B cell lymphoma and
• Trastuzumab is used for breast cancer treatment.
MONOCLONAL ANTIBODIES

56. COMMON SIDE EFFECTS OF MAB
• Fever
• Chills
• Weakness
• Headache
• Nausea
• Vomiting
• Diarrhoea
• Low blood pressure
• Rashes

57. ENDOCRINE THERAPIES
• Selective Estrogen Receptor
Modulators:
 Tamoxifen
 Raloxifen
 Torimefene
• Androgens
 Fluoxymesterone
• Progestin
 Megestrol acetate
 Medroxyprogesterone
acetate
• High dose Estrogens
• Aromatase inhibitors:
 Letrozole
 Anastrazole
 Exemestane
• Steroidal Antiestrogens:
 Fulvestrant
• LHRH agonists
 Leuprolide
 Goserelin
• Gland ablation
 Ovary
 Pituitary

58. Ovary
Pituitary gland
LHRH
(hypothalamus)
Pre-/post-
menopausal
Premenopausal
Gonadotrophins
(FSH + LH)
ACTH
Adrenal
glands
Oestrogens
Progesterone
Progesterone
Androgens Oestrogens
Peripheral conversion
ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone;
LH, luteinising hormone; LHRH, LH releasing hormone
LHRHa
Aromatase Inhibitors
Hormonal mechanism
Ovary

59. OXYGEN EFFECT AND CHEMOTHERAPEUTIC AGENTS

61. ADJUNCT USE OF CHEMOTHERAPEUTIC AGENTS
WITH RADIATION
• The initial rationale for the combination of radiation and chemotherapeutic
agents was what is usually known as “spatial cooperation”.
• Chemotherapy is the primary treatment modality, and radiation is used
only to treat “sanctuary” sites not reached by the drug.

62. • Although spatial cooperation was the original rationale, it is no longer the
only one.
• Cells in the G2 and M cell cycle phases were approximately three times
more sensitive to Radiation than cells in the S phase.
 The drugs that can block transition of cells through mitosis, with the
result that cells accumulate in the radiosensitive G2 and M phases of
the cell cycle
 e.g- Taxanes
 Elimination of the radioresistant S-phase cells by the
chemotherapeutic agents.
 e.g- Nucleoside analogs, such as fludarabine or gemcitabine

63. • to graded doses of γ-rays alone and after a 24-hour
treatment with a 10-nM concentration of paclitaxel. This drug
concentration killed 95% of the cells and, as indicated by the
inset, synchronized the survivors in the radiosensitive phase
of the cell cycle.

64. • In general, a therapeutic gain requires differential effects
between tumor and normal tissue. One or more of the
following tumor characteristics may be exploited to achieve
this difference:
1. Genetic instability of tumor cells
2. Rapid proliferation of some tumor cells
3. Cell age distribution of tumor cell populations
4. Hypoxia (characteristic of larger tumors)
5. pH (often low in tumors)
6. Elevation of specific pathways in tumors (e.g., EGFR)

65. SECOND MALIGNANCY

66. THANK YOU