This document discusses various modalities for treating cancer including chemotherapy. It provides details on the mechanisms of action, goals and classifications of different chemotherapeutic agents. It describes how certain drugs like methotrexate, cyclophosphamide and cisplatin directly damage DNA to inhibit cell proliferation. It also discusses concepts like drug resistance, cell cycle specificity and overcoming resistance through combination therapy. The document concludes by summarizing adverse effects of major drug classes and approaches to manage toxicities.

1. Presenters:
DR. RENESHA ISLAM
DR. MOMTAHINA MOU
YEAR-3 RESIDENT (PHASE-B)
PAEDIATRIC HAEMATOLOGY & ONCOLOGY
BANGABANDHU SHEIKH MUJIB MEDICAL UNIVERSITY
CANCER
CHEMOTHERAPY

2. Modalities of
treatment in cancer
• Surgery
• Radiotherapy
• Chemotherapy: >50 % of the patients can
be treated with chemotherapy
contributing to cure in 15 -20 % of
patients.

3. Cancer can be cured by
chemotherapy
• Acute Leukemias
• Wilm’s Tumour
• Ewing’s Sarcoma
• Hodgkin’s Disease
• Burkitts lymphoma
• GCT

4. Goals of chemotherapy
• Wilm’s tumor, ALL, Testicular
cancer, Burkitt’s lymphoma,
NHL
To Cure
• Prolong remission
• Decreases rate of relapse
To Control
• Relive symptoms and
improved quality of life
Palliation

5.  Certain chemotherapeutic agents also have a
role in the treatment of other conditions,
including :
• Ankylosing spondylitis
• Multiple sclerosis
• Crohn's disease
• Psoriasis, psoriatic arthritis
• Systemic lupus erythematosus
• JIA and
• Scleroderma.

6. Basic concepts of cancer cell
growth
• Cell life cycle and
drug
• Log kill hypothesis
• Growth fraction
• Tumour burden

8. Cell cycle and drugs
G1 – L- Asparginase
S – Methotrexate
6-Mercaptopurine
5-Fluorouracil
Mitomycin C
Hydroxyurea
Doxorubicin
G2 – Bleomycin
Etoposide,
Topotecan
Daunorubicin
M – Vincristine
Vinblastine
Paclitaxel,
Docetaxel

10. Log kill hypothesis
• Cell kill by first order kinetics.
• A constant fraction of cells are killed by a given
drug dose, not constant number.
• A constant percentage of the total number of
cancer cells present in tumor will be killed with
each course of chemotherapy.
• Hence repeated doses of chemotherapy must be
used for total cells kill.

11. Tumor regrowth after
premature Cessation of
Therapy.

12. Growth fraction
Growth fraction is the percentage of actively dividing cells at
any given point in time.
1. High growth fraction tumour : more sensitive to cycle-
specific drugs.
e.g. 1. leukemia and lymphoma
2. Normal with tissues high growth fraction like bone
marrow, hair follicles, and intestinal.
2. Low growth fraction tumour : Solid tumour e.g. carcinomas
of the colon, lung cancer) are less responsive to cycle-specific
drugs.

13. Tumour burden
• The tumor burden is the size of the tumor as
determined by the number of cells present.
• Small tumor burden → more responsive
• Higher the tumor burden → probability of drug
resistance.
• Cancer cells usually follows Gompertzian growth
pattern.

14. Gompertzian Growth

15. Gompertzian Growth
It is model of cancer cell growth.
“Cell rapidly divide early in life, then plateaus.”
Significance :
1. Most anticancer drugs are ineffective in
advanced cancers which have very low growth
fraction.
2. Debulking procedures makes tumour again
responsive to drugs by inducing remaining cells to
divide.

16. Terminology used in
describing chemotherapy
• Induction: High-dose, usually combination,
chemotherapy given with the intent of inducing
complete remission when initiating a curative
regimen. The term is usually applied to hematologic
malignancies but is equally applicable to solid
tumors.
• Consolidation: Repetition of the induction regimen
in a patient who has achieved a complete remission
after induction, with the intent of increasing cure
rate or prolonging remission.

17. Continued…….
• Intensification: Chemotherapy after complete
remission with higher doses of the same agents used
for induction or with different agents at high doses
with the intent of increasing cure rate or remission
duration.
• Maintenance: Long-term, low-dose, single or
combination chemotherapy in a patient who has
achieved a complete remission, with the intent of
delaying the regrowth of residual tumor.

18. Continued…….
• Adjuvant: A short course of high-dose, usually
combination chemotherapy in a patient with no
evidence of residual cancer after surgery or
radiotherapy, given with the intent of destroying a
low number of residual tumor cells.
• Neoadjuvant: Adjuvant chemotherapy given in the
preoperative period.
• Palliative: Chemotherapy given to control symptoms
or prolong life in a patient in whom cure is unlikely.

19. Principles of
combination therapy
Combination therapy involves the use of two or more
drugs proven effective against a tumor type.
Major advances in cancer treatment in the past 20
years.
RATIONALE OF COMBINATION CHEMOTHERAPY
• Prevention of resistant clones.
• Cytotoxicity to resting and dividing cells.
• Biochemical enhancement or effect –
Synergistic effect

20. 2 major challenges to Chemotherapy
1. Toxic side effects
2. Drug resistance
Challenges to
Chemotherapy

21. Resistance to
chemotherapeutic agents
Resistance constitutes a lack of response to drug-
induced tumour growth inhibition
1. Primary resistance: No response from very first
exposure.
e.g. malignant melanoma, renal tumours.
2. Acquired resistance : During continuation of therapy.
Due to adaption of tumour cells or due to mutation
in one or more gene.

22. 1. ↑ drug efflux via P-glycoprotein transporters e.g. doxorubicin,
paclitaxel, vincristine, etoposide
2. Overexpression of the multidrug resistance protein 1(MRCP1) →
↑resistance to natural drugs e.g. Vinca alkaloid, Anthracyclins.
3. ↓ inward transport e.g. Methotrexate
4. Insufficient activation of the drug (e.g. Mercaptopurine ,
Fluorouracil and Cytarabine.
5. Increase in inactivation (e.g. Cytarabine and Mercaptopurine )
6. Increased concentration of target enzyme (Methotrexate)
7. Rapid repair of drug-induced lesions (Alkylating agents).
8. Altered activity of target proteins, for example modified
topoisomerase II (Doxorubicin).
Mechanism of
resistance

23. • Use of combination drug therapy using different
classes of drugs with different mechanism of
action.
• With narrowest cycle intervals, necessary for
bone marrow recovery.
• Drugs that reverse multidrug resistance include
verapamil, quinidine, and cyclosporine .
Overcoming resistance

24. Classification Of Anti-cancer
Drugs

26. Purine Synthesis Pyrimidine Synthesis
Ribonucleotides
Deoxyribonucleotides
DNA
RNA
Proteins
Enzymes Microtubules
6-Mercaptopurine
6-Thioguanine
Methotrexate → DHFR
5-Fluorouracil
Cytarabine
Gemcitabine
Hydroxyurea
Etoposide
Topoisomerase II
Inhibitor- DNA break
Antibiotics
L-Asparaginase
Vinca Alkaloids →
prevent
polymerization
Antimetabolites
Alkylating agents
Alkylation→ Alter
structure & function of
DNA by cross linking
and/or fragmenting DNA
MOA of some anticancer drugs

27. Alkylating Agents

28. 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

29. Cyclophosphamide
Cyclophosphamide
Aldophosphamide
Phosphoramide
mustard
Acrolein
Cytotoxic effect
Hemorrhagic cystitis
MESNA


30. Cyclophosphamide /Ifosfamide
• Adverse effects:
– Alopecia,
– Nausea & Vomiting,
– SIADH
– Nephrotoxic
– Secondary malignancy-AML
– Hemorrhagic cystits-This effect is dose related
and caused by the activated metabolites such as
acrolein which causes chemical cystitis.

31. Contd.
Hemorrhagic cystitis can be
prevented by
• Hydration
• Frequent emptying of bladder
• Bladder irrigation
• Administration of MESNA (2-
matrcaptoethane sulfonate
Na) .Dose-equal to 60% of the
total ifosfamide dose divided
in to four dose.

32. Cisplatin enters cells
Forms highly reactive platinum complexes
DNA damage
Intra strand & interstrand cross links
Inhibits cell proliferation
Cl-
Mechanism of action of
Cisplatin

33. • Adverse effects
– Emesis
– Nephrotoxicity
– Peripheral neuropathy
– Ototoxicity
– Myelosuppressoin
– SIADH
Post cisplatin hydration
Adverse effects

34. • Folate Antagonists
–Methotrexate
• Purine Antagonists
–6 Mercaptopurine, 6 Thioguanine,
Azathioprine
• Pyrimidine antagonists
–5 Fluorouracil, cytarabine, gemcitabine
Antimetabolites

35. Methotrexate
Adenine, guanine,
thymidine ,
methionine, serine
Folic acid not
useful in toxicity
Folinic acid N5 formyl
FH4 should be given
which is converted to
N5,N10-Methylene –FH4
and bypasses the
inhibited reductase

36. Adverse effects
• Myelosuppression
• Mucositis
•Nephrotoxicity
• Acute cerebellar dysfunction
•Acute chemical arachnoidits
with headache, nuchal rigidity, seizures, vomiting,
fever after intrathecal administration

37. Preventions of MTX toxicity
• Hydration (starting 12 hours before and 24-48
hours after MTX infusion)
• Alkalization of urine (sodium bicarbonate in IV
fluid to ensure that urinary pH>7)
• Inj.Folinic Acid- start 24 hours after MTX
infusion, 6 hourly 6 doses
• Oral care.

38. Purine antagonists
• 6 Mercaptopurine
• 6 Thioguanine
• Azathioprine
• Fludarabine

39. HGPRT
6 Mercaptopurine
Ribonucleotide
(HGPRT):
hypoxanthine-guanine
phosphoribosyl
transferase

40. 6 Mercaptopurine
• Adverse Effects:
– Myelosuppression
– Mucositis
– Hepatotoxic
– Dry skin
– Urticaria
– Photosensitivity

41. Pyrimidine antagonists
• 5 fluoruracil
• Cytosine arabinoside (Cytarabine)
• Gemcitabine .

42. 5 fluorouracil
5 FU FdUMP
dUMP
Thymidine
Monophosphate
Thymidilate
synthetase
DNA Synthesis
(Selective failure)
Uses : stomach , colon,
breast ovaries , liver, skin
cancers
FdUMP = fluorodeoxyuridine
monophosphate

43. Adverse effect
• Myelosuppression
• Mucositis
• Hand-foot syndrome (tingling, numbness, pain, erythema,
dryness, pruritis of the hand and feet and desquamation)
• Neurotoxicity (Confusion, Seizure, Cerebellar ataxia)
• Blepharitis
• Acute & chronic conjunctivitis.

44. Cytosine arabinoside
• Pyrimidine analog, cell cycle specific
• Mechanism of action:
Phosphorylated in body to triphosphate
Triphosphate of cytarabine inhibits DNA polymerase 
& 
Thus inhibit DNA synthesis and repair.

45. Adverse effect
• Myelosuppression
• Nausea & vomiting
• Neurotoxicity (cerebellar ataxia,lethargy & confusion)
• Ara-c syndrome (fever, myalgia, bone pain,
maculopapular rash, conjunctivitis, chest pain)
• Conjunctivitis and keratitis ( Mx. Steroid eye drop)
• Acute pancreatitis
• Pulmonary complication (ARDS, pulmonary oedema)

46. Vinca alkaloids
• Obtained from periwinkle plant ( Vinca Rosea)
 Vincristine
 Vinblastine
 Vindesine
 Vinorelbine

47. Mechanism of action

48. Adverse effect
• Neurotoxicity (peripheral neuropathy, cranial nerve
palsy, seizure, bone pain, jaw pain)
• Constipation
• Abdominal pain, paralytic ileus.
• Vesicant- Extravsation may causes local tissue injury
and necrosis
• SIADH

49. Management of extravasation
• Immediately discontinue infusion
• Application of hot compression
• Elevation of the extremity
• Local application- Hyaluronidase.

50. Epipodophyllotoxins
Semisynthetic derivatives of podophyllotoxins
podophyllum peltatum (plant glycoside)
 Etoposide &
 tenoposide

51. Etoposide
• Act in late S & G2 phase
• Inhibit topoisomerase II which results in
breakage of DNA strands & cell death.

52. Adverse effect
• Myelosuppression
• Nausea and vomiting
• Alopecia
• Radiation-recall skin change
• Secondary malignancies- AML

53. Doxorubicin & Daunorubucin

54. Adverse effect
• Myelosuppression
• Nausea and vomiting
• Mucositis and diarrhea
• Cardiotoxicity- Acute form presents within first 2-3
days as arrythmia, conduction abnormalities,
pericarditis, myocarditis
• Chronic form- Dilated cardiomyopathy, CCF
(cumulative dose>450mg/m2)

55. Management of toxicity
• If extravation- Immediately stop infusion, elevate
extremity and apply ice.may administer local steroid.
• Risk of cardiotoxicity higher child younger than 5 yrs,
pre-existing heart diseases,prior radiation therapy.
• Cardiotoxic effect of doxorubicin are inhibited by the
iron chelating agent dexrazoxane (dose 10mg for 1mg
doxorubicin)

56. Contd.
• Enalapril (ACE inhibitor) prevent the late
decline LVEF.
• Carvidilol (beta blocker) has cardioprotective
effect through its anti oxidant properties.

57. Bleomycin
Reacts with iron, copper
& O2 in presence of CYP -
450 reductase
Also can intercalate
between DNA strands
DNA – bleomycin – Fe2+
DNA – bleomycin – Fe3+

58. Bleomycin
• Adverse effects:
 Skin reaction (erythema, hyperpigmentation,
vesiculation, skin peeling, hyperkeratosis)
 Pulmonary toxicity (pneumonitis, pulmonary
fibrosis-cumulative dose>400 unit)
 Hypersensitivity reaction(fever, chills)

59. L-asparaginase

60. E.coli Erwinia PGE
Derived from Eschrerichia
coli
Erwinia
carotovora
Conjugation poly
ethylene glycol to
E.coli
Half life 24-36 hr 10-15hr 5-7days
Peak
concentration
24-48hr <24hr 72-96hr
Immuno-
genicity
More than
PGE
More than PGE Less than both
native forms

61. Adverse effect
• Hypersensitivity
• Fever, chills, nausea and vomiting
• Coagulation abnormality (decrese level of
clotting factor)
• Pancreatitis
• Neurologic toxicity (lethargy, confusion,
hallucination)
• Renal toxicity

62. Glucocorticoids
• Marked lympholytic effect so used in acute leukaemias
& lymphomas,
• They also
– Have Anti-inflammatory effect
– Increase appetite, prevent anemia
– Produce sense of well being
– Increase body weight
– Supress hypersensitivity reaction
– Control hypercalcemia & bleeding
– Non specific antipyretic effect
– Increase antiemetic effect of ondansetron

64. ATRA
• Tretinoin binds to the
cytoplasmic protein (CRABP)-
retinoid CRABP complex
transported to the nucleus-
binds to retinoid receptors
RAR/RXR-affect the
transcription and subsequent
expression of various target
cellular gene involved in
growth,proliferation and
differentiation.

65. Adverse effect
• Headache, cheilitis, dry mouth,
xerosis, pruritus, bone & joint pain
• Retinoic acid syndrome-fever, wt
gain, respiratory distress, serous
effusion, pulmonary infiltrates,
leukocytosis
• Increased serum cholesterol &
triglyceride level
• GI toxicity-abdominal pain,
constipation, diarrhea
• Pseudotumor cerebri

66. Stability of drugs
• Carboplatin- Reconstituted solution is stable for 8
hours at room temperature 25°c.
• Cisplatin- After dilution stable for 72 hours at 4°c-
25°c.
• Cyclophosphamide- After dilution stable for 24 hours
at room tem.& 6 days in the refrigerator.

67. Contd.
• Ifosphamide- Reconstitued solution used within 72
hours when refrigerated in glass bottle.
• Doxorubicin- Reconstituted solution is stable for 7
days at(15°c-25°c) and 15 days at(2°c-8°c).
• Vincristine- Unused solution should be discarded.