This document discusses various classes of chemotherapeutic agents used to treat cancer, including their mechanisms of action, toxicities, and therapeutic uses. It covers cell cycle specific and non-specific agents such as antimetabolites like methotrexate and 5-fluorouracil, alkylating agents like cyclophosphamide, plant alkaloids like vincristine, and antibiotics like doxorubicin. Resistance mechanisms such as drug efflux pumps and how to manage toxicities are also addressed.

1. Cancer
Chemotherapy
Jillian H. Davis
Department of Pharmacology
Howard University

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

4. Resistance to Cytotoxic Drugs
 Increased expression of MDR-1 gene for a cell
surface glycoprotein, P-glycoprotein
 MDR-1 gene is involved with drug efflux
 Drugs that reverse multidrug resistance include
verapamil, quinidine, and cyclosporine
 MDR increases resistance to natural drug products
including the anthracyclines, vinca alkaloids, and
epipodophyllotoxins

5. Schematic of P-glycoprotein

6. Alkylating Agents
Nitrogen Mustards Ethylenimines Alkyl Sulfonates Nitrosoureas
Cyclophosphamide Thiotepa Busulfan Carmustine
Legend
Drug Class
Sub-class
Prototype Drug

7. Alkylating Agents
Mechanism of Action
 Alkylate within DNA at the N7 position of
guanine
 Resulting in miscoding through abnormal
base-pairing with thymine or in
depurination by excision of guanine
residues, leading to strand breakage
 Cross-linking of DNA and ring cleavage
may also occur

8. Alkylating Agents
Mechanism of Action

9. Nitrogen Mustards
 Cyclophosphamide
 Ifosfamide
 Mechlorethamine
 Melphalan
 Chlorambucil

10. Cyclophosphamide Metabolism

11. Nitrosoureas
 Carmustine
 Lomustine
 Semustine
 Streptozocin-naturally occuring sugar
containing
M.O.A.- cross-link through alkylation of DNA
All cross the blood brain barrier

12. Alkylating-Related Agents
 Procarbazine
 Dacarbazine
 Altretamine
 Cisplatin
 Carboplatin

13. Platinum Coordination
Complexes
These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity.
To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic,
or induce chloride diuresis with 0.1% NaCl.

14. Alkylating Agents
Toxicity
 Bone marrow depression, with leukopenia and
thrombocytopenia
 Cyclophosphamide/Ifosfamide - hemorrhagic
cystitis
 Reduced by coadministration with MESNA
 Cisplatin/Carboplatin - ototoxic and nephrotoxic
 Nephrotoxicity reduced by chloride diuresis and hydration

15. Alkylating Agents
Therapeutic Uses
 Used to treat a wide variety of hematologic and
solid tumors
 Thiotepa – ovarian cancer
 Busulfan – chronic myeloid leukemia
 Nitrosoureas - brain tumors
 Streptozocin – insulin-secreting islet cell
carcinoma of the pancreas

16. Antimetabolites
Folic Acid Analogs Purine Analogs Pyrimidine Analogs
Methotrexate Mercaptoguanine Fluorouracil
Legend
Drug Class
Sub-class
Prototype Drug

17. Folic Acid Analogs
 Methotrexate
 Trimetrexate
 Pemetrexed

18. Folate
 An essential dietary factor, from which
THF cofactors are formed which
provide single carbon groups for the
synthesis of precursors of DNA and
RNA
 To function as a cofactor folate must be
reduced by DHFR to THF

19. Methotrexate
Mechanism of Action
 The enzyme DHFR is the 1º site of action
 MTX prevents the formation of THF, causing
an intracellular deficiency of folate
coenzymes and accumulation of the toxic
inhibitory substrate, DHF polyglutamate
 The one carbon transfer reactions for purine
and thymidylate synthesis cease,
interrupting DNA and RNA synthesis

20. Major Enzymatic Reactions Requiring Folates as
Substrates*
GAR transformylase AICAR transformylase AMP
GAR AICAR IMP
GMP
(3)
10-formylTHF
(2)
Formate Methionine
b +
DHF THF
e
(1) c d
dTMP 5,10-CH2THF 5-CH3THF
a Homocysteine
DNA dUMP
a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase;
*from Bowen d, methionine synthase; e, serine hydroxymethyl transferase

21. Resistance

22. Methotrexate
Mechanism of Resistance
1. Decreased drug transport
2. Altered DHFR
3. Decreased polyglutamate formation
4. Increased levels of DHFR

23. Methotrexate
Therapeutic Uses
 Methotrexate- psoriasis, rheumatoid
arthritis, acute lymphoblastic leukemia,
meningeal leukemia, choriocarcinoma,
osteosarcoma, mycosis fungoides,
Burkitt’s and non-Hodgkin’s
lymphomas, cancers of the breast,
head and neck, ovary, and bladder

24. Trimetrexate
Therapeutic Uses
 Trimetrexate- Pneumocystis carinii
pneumonia, metastatic colorectal
carcinoma, head and neck carcinoma,
pancreatic carcinoma, non-small cell
carcinoma of the lung

25. Pemetrexed
Therapeutic Uses
 Pemetrexed- Mesothelioma

26. Methotrexate
Toxicity
 Bone marrow suppression
 Rescue with leucovorin (folinic acid)
 Nephrotoxic
 give sodium bicarbonate to alkalinize the
urine

27. Purine Antagonists
 Mercaptopurine
 Thioguanine
 Fludarabine Phosphate
 Cladribine

28. Mercaptopurine/Thioguanine
 Must metabolized by HGPRT to the
nucleotide form
 This form inhibits numerous enzymes of
purine nucleotide interconversion

29. Fludarabine Phosphate
 M.O.A.- phosphorylated intracellularly by
deoxycytidine kinase to the triphosphate
form
 The metabolite inhibits DNA polymerase-α
and ribonucleotide reductase
 Induces apoptosis
 Tx- non-Hodgkin’s lymphoma and chronic
lymphocytic leukemia

30. Cladribine
 M.O.A. -phosphorylated by deoxycytidine
kinase and is incorporated into DNA
 Causes DNA strand breaks
 Tx- hairy cell leukemia, chronic
lymphocytic leukemia, and non-Hodgkin’s
lymphoma

31. Pyrimidine Antagonists
 Fluorouracil - S-phase
 Cytarabine
 Gemcitabine
 Capecitabine

32. MTX X
5-FU
X
Figure 2. This figure illustrates the effects of MTX and 5-FU on the
biochemical pathway for reduced folates.

33. Mechanism of Action 5-FU
 5-FU inhibits thymidylate synthase
therefore causing depletion of
Thymidylate
 5-FU is incorporated into DNA
 5-FU inhibits RNA processing

34. Activation of 5-FU

35. Therapeutic Uses of 5-FU
 Metastatic carcinomas of the breast and
the GI tract
 hepatoma
 carcinomas of the ovary, cervix, urinary
bladder, prostate, pancreas, and
oropharyngeal areas
 Combined with levamisole for Tx of colon
cancer

36. Cytarabine
 It is activated to 5’ monophosphate
(AraCMP) by deoxycytidine kinase
 Through a series of reactions it forms
the diphosphate (AraCDP) and
triphosphate (AraCTP) nucleotides
 Accumulation of AraCTP potently
inhibits DNA synthesis
 Inhibition of DNA synthesis is due to
competitive (-) of polymerases and
interference of chain elongation

37. Cytarabine
 It is a potent inducer of tumor cell
differentiation
 Fragmentation of DNA and evidence of
apoptosis is noticed in treated cells
 AraC is cell-cycle specific agent, it kills
cells in the S-phase

38. Cytarabine
Mechanisms of Resistance
 deficiency of deoxycytidine kinase
 increased CTP synthase activity
 increased cytidine deaminase activity
 decreased affinity of DNA polymerase for
AraCTP
 decrease ability of the cell to transport
AraC

39. Cytarabine
Therapeutic Uses
 Induction of remissions in acute leukemia
 Treats meningeal leukemia
 Treatment of acute nonlymphocytic
leukemia
 In combination with anthracyclines or
mitoxantrone it can treat non-Hodgkin’s
lymphomas

40. Cytarabine
Toxicities
 Nausea
 acute myelosuppression
 stomatitis
 alopecia

41. Gemcitabine
 Gemcitabine is S-phase specific
 it is a deoxycytidine antimetabolite
 it undergoes intracellular conversion to
gemcitabine monophosphate via the
enzyme deoxycytidine kinase
 it is subsequently phosphorylated to
gemcitabine diphosphate and gemcitabine
triphosphate

42. Gemcitabine
 Gemcitabine triphosphate competes with
deoxycytidine triphosphate (dCTP) for
incorporation into DNA strands
 do to an addition of a base pair before
DNA polymerase is stopped, Gemcitabine
inhibits both DNA replication and repair
 Gemcitabine-induced cell death has
characteristics of apoptosis

43. Gemcitabine
Therapeutic Uses
 Gemcitabine treats a variety of solid
tumors
 very effective in the treatment of
pancreatic cancer
 small cell lung cancer
 carcinoma of the bladder, breast, kidney,
ovary, and head and neck

44. Cancer
Chemotherapy
Jillian H. Davis
Department of Pharmacology
Howard University

45. Plant Alkaloids
Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes
Vinblastine Etoposide Topotecan Paclitaxel

46. Vinca Alkaloids
 Vinblastine
 Vincristine
 Vinorelbine

47. Vinca Alkaloids
Inhibit microtubules
(spindle), causing
metaphase cell arrest
in M phase.
3
3

48. Vinca Alkaloids
Mechanism of Action
 Binds to the microtubular protein tubulin in a
dimeric form
 The drug-tubulin complex adds to the forming
end of the microtubules to terminate assembly
 Depolymerization of the microtubules occurs
 Resulting in mitotic arrest at metaphase,
dissolution of the mitotic spindle, and
interference with chromosome segregation
 CCS agents- M phase

49. Vinblastine
Toxicity
 Nausea
 Vomiting
 Marrow depression
 Alopecia

50. Vinblastine
Therapeutic Uses
 Systemic Hodgkin’s disease
 Lymphomas

51. Vincristine
Toxicity
 Muscle weakness
 Peripheral neuritis

52. Vincristine
Therapeutic Uses
 With prednisone for remission of Acute
Leukemia

53. Vinorelbine
Toxicity
 Granulocytopenia
Therapeutic Uses
 non-small cell lung cancer

54. Podophyllotoxins
 Etoposide (VP-16)
 Teniposide (VM-26)
 Semi-synthetic derivatives of podophyllotoxin extracted
from the root of the mayapple

55. Podophyllotoxins
Mechanism of Action
 Blocks cells in the late S-G2 phase of the
cell cycle through inhibition of
topoisomerase II
 Resulting in DNA damage through strand
breakage induced by the formation of a
ternary complex of drug, DNA, and
enzyme

56. Podophyllotoxins
Toxicity
 Nausea
 Vomiting
 Alopecia
 Hematopoietic and lymphoid toxicity

57. Podophyllotoxins
Therapeutic Uses
 Monocytic Leukemia
 Testicular cancer
 Oat cell carcinoma of the lung

58. Camptothecins
 Topotecan
 Irinotecan

59. Camptothecins
Mechanism of Action
 Interfere with the activity of Topoisomerase I
 Resulting in DNA damage
 Irinotecan- a prodrug that is metabolized to
an active Top I inhibitor, SN-38

60. Camptothecins
Toxicity
 Topotecan
 Neutropenia, thrombocytopenia, anemia
 Irinotecan
 Severe diarrhea, myelosuppression

61. Camptothecins
Therapeutic Uses
 Topotecan- metastatic ovarian cancer
(cisplatin-resistant)
 Irinotecan- colon and rectal cancer

62. Taxanes
 Paclitaxel (Taxol)
 Docetaxel
 Alkaloid esters derived from the Western
and European Yew

63. Taxanes
Mechanism of Action
 Mitotic “spindle poison” through the
enhancement of tubulin polymerization

64. Taxanes
Toxicity
 Paclitaxel
 Neutropenia, thrombocytopenia
 Peripheral neuropathy
 Docetaxel
 Bone marrow suppression
 Neurotoxicity
 Fluid retention

65. Taxanes
Therapeutic Uses
 Paclitaxel- ovarian and advanced breast
cancer
 Docetaxel- advanced breast cancer

66. Antibiotics
 Anthracyclines- Doxorubicin &
Daunorubicin
 Dactinomycin
 Plicamycin
 Mitomycin
 Bleomycin

67. Anthracyclines
 Doxorubicin
 Daunorubicin

68. Anthracyclines
Mechanism of Action
 High-affinity binding to DNA through
intercalation, resulting in blockade of DNA
and RNA synthesis
 DNA strand scission via effects on Top II
 Binding to membranes altering fluidity
 Generation of the semiquinone free radical
and oxygen radicals

69. Anthracyclines
Toxicity
 Bone marrow depression
 Total alopecia
 Cardiac toxicity

70. Anthracyclines
Therapeutic Uses
 Doxorubicin- carcinomas of the breast,
endometrium, ovary, testicle, thyroid, and
lung, Ewing’s sarcoma, and osteosarcoma
 Daunorubicin- acute leukemia

71. Dactinomycin
Mechanism of Action
 Binds to double stranded DNA through
intercalation between adjacent guanine-
cytosine base pairs
 Inhibits all forms of DNA-dependent RNA
synthesis

72. Dactinomycin
Toxicity
 Bone marrow depression
 Oral ulcers
 Skin eruptions
 Immunosuppression

73. Dactinomycin
Therapeutic Uses
 Wilms’ tumors
 Gestational choriocarinoma with MTX

74. Plicamycin
Mechanism of Action
 Binds to DNA through an antibiotic-Mg2+
complex
 This interaction interrupts DNA-directed
RNA synthesis

75. Plicamycin
Toxicity
 Hypocalcemia
 Bleeding disorders
 Liver toxicity

76. Plicamycin
Therapeutic Uses
 Testicular cancer
 Hypercalcemia

77. Mitomycin
Mechanism of Action
 Bioreductive alkylating agent that
undergoes metabolic reductive activation
through an enzyme-mediated reduction to
generate an alkylating agent that cross-
links DNA

78. Mitomycin
Toxicity
 Severe myelosuppression
 Renal toxicity
 Interstitial pneumonitis

79. Mitomycin
Therapeutic Uses
 Squamous cell carcinoma of the cervix
 Adenocarcinomas of the stomach,
pancreas, and lung
 2nd line in metastatic colon cancer

80. Bleomycin
 Acts through binding to DNA, which
results in single and double strand breaks
following free radical formation and
inhibition of DNA synthesis
 The DNA fragmentation is due to oxidation
of a DNA-bleomycin-Fe(II) complex and
leads to chromosomal aberrations
 CCS drug that causes accumulation of
cells in G2

81. Bleomycin
Toxicity
 Lethal anaphylactoid reactions
 Blistering
 Pulmonary fibrosis

82. Bleomycin
Therapeutic Uses
 Testicular cancer
 Squamous cell carcinomas of the head
and neck, cervix, skin, penis, and rectum
 Lymphomas
 Intracavitary therapy in ovarian and breast
cancers

83. Hormonal Agents
Estrogen & Androgen Gonadotropin-Releasing Aromatase Inhibitors
Inhibitors Hormone Agonists
Tamoxifen Leuprolide Aminogluthethimide
Legend
Drug Class
Sub-class
Prototype Drug

84. Anti-Estrogens
 Tamoxifen (SERMs)
 Raloxifene (SERMs)
 Faslodex

85. Tamoxifen
 Selective estrogen receptor modulator (SERM), have both
estrogenic and antiestrogenic effects on various tissues
 Binds to estrogen receptors (ER) and induces conformational
changes in the receptor
 Has antiestrogenic effects on breast tissue.
 The ability to produce both estrogenic and antiestrogenic
affects is most likely due to the interaction with other
coactivators or corepressors in the tissue and the binding with
different estrogen receptors, ERα and ERβ
 Subsequent to tamoxifen ER binding, the expression of
estrogen dependent genes is blocked or altered
 Resulting in decreased estrogen response.
 Most of tamoxifen’s affects occur in the G1 phase of the cell
cycle

86. Tamoxifen
Toxicity
 Hot flashes
 Fluid retention
 nausea

87. Tamoxifen
Therapeutic Uses
 Tamoxifen can be used as primary therapy for
metastatic breast cancer in both men and
postmenopausal women
 Patients with estrogen-receptor (ER) positive
tumors are more likely to respond to tamoxifen
therapy, while the use of tamoxifen in women
with ER negative tumors is still investigational
 When used prophylatically, tamoxifen has been
shown to decrease the incidence of breast
cancer in women who are at high risk for
developing the disease

88. Anti-Androgen
 Flutamide
 Antagonizes androgenic effects
 approved for the treatment of prostate cancer

89. Gonadotropoin-Releasing Hormone
Agonists
 Leuprolide
 Goserelin

90. Gonadotropoin-Releasing Hormone
Agonist
Mechanism of Action
 Agents act as GnRH agonist, with
paradoxic effects on the pituitary
 Initially stimulating the release of FSH and
LH, followed by inhibition of the release of
these hormones
 Resulting in reduced testicular androgen
synthesis

91. Gonadotropoin-Releasing Hormone
Agonist
Toxicity
 Gynecomastia
 Edema
 thromboembolism

92. Gonadotropoin-Releasing Hormone
Agonist
Therapeutic Uses
 Metastatic carcinoma of the prostate
 Hormone receptor-positive breast cancer

93. Aromatase Inhibitors
 Aminogluthethimide
 Anastrozole

94. Aminogluthethimide
Mechanism of Action
 Inhibitor of adrenal steroid synthesis at the
first step, conversion of cholesterol of
pregnenolone
 Inhibits the extra-adrenal synthesis of
estrone and estradiol
 Inhibits the enzyme aromatase that
converts androstenedione to estrone

96. Aminogluthethimide
Toxicity
 Dizziness
 Lethargy
 Visual blurring
 Rash
Therapeutic Uses
 ER- and PR-positive metastatic breast
cancer

97. Anastrozole
 A new selective nonsteroidal inhibitor of
aromatase
 Treats advanced estrogen and
progesterone receptor positive breast
cancer that is no longer responsive to
tamoxifen

98. Miscellaneous AntiCancer Agents
 Asparaginase
 Hydroxurea
 Mitoxantrone
 Mitotane
 Retinoic Acid Derivatives
 Amifostine

99. Asparaginase
 An enzyme isolated from bacteria
 Causes catabolic depletion of serum
asparagine to aspartic acid and ammonia
 Resulting in reduced blood glutamine levels
and inhibition of protein synthesis
 Neoplastic cells require external source of
asparagine
 Treats childhood acute leukemia
 Can cause anaphylactic shock

100. Hydroxyurea
 An analog of urea
 Inhibits the enzyme ribonucleotide reductase
 Resulting in the depletion of
deoxynucleoside triphosphate pools
 Thereby inhibiting DNA synthesis
 S-phase specific agent
 Treats melanoma and chronic myelogenous
leukemia

101. Mitoxantrone
 Structure resembles the anthracyclines
 Binds to DNA to produce strand breakage
 Inhibits DNA and RNA synthesis
 Treats pediatric and adult acute
myelogenous leukemia, non-Hodgkin’s
lymphomas, and breast cancer
 Causes cardiac toxicity

102. Mechanisms & Actions of Useful
Chemotherapeutic Drugs in Neoplastic
Disease