Anti-Cancer drugs

1. ANTICANCERANTICANCER
DRUGSDRUGS

2. Possible causes of cancer
•Physical agents (radiation,
mobile phones ?)
•Chemicals
(carcinogens, including
smoking)
•Hereditary factors
•Effectiveness of the immune system
(virus infections: Ca collum uteri)
•Stress, > BMI (GI cancer),
•some drugs (cyclophosphamide,
estrogens, tamoxifen)

3. •Uncontrolled proliferation
•Can be invasive
•Can metastasize
•Lack of function
(lack of differentiation)
Characteristics
of cancer cells

4. Normal cells
•Growth is controlled
by growth factors
and growth
inhibitory factors
Cancer cells
•Inactivation of
tumor-suppressor genes
•Activation of proto-oncogenes

5. Sponsored
Medical Lecture Notes – All Subjects
USMLE Exam (America) – Practice

6. ANTICANCERANTICANCER
TREATMENTTREATMENT
 surgerysurgery
 radiotherapyradiotherapy
(irradiation)(irradiation)
 chemotherapychemotherapy
 supportive therapiessupportive therapies
NB!NB!
NB!

7. TheThe sensitivitysensitivity ofof
a cancer to treatmenta cancer to treatment
depends on thedepends on the
growth fractiongrowth fraction ––
that is the fractionthat is the fraction
of cells undergoingof cells undergoing
mitosismitosis at any time.at any time.

8. The fraction of cell division
in Burkitt’s lymphoma is 100%
and this tumor is very sensitive.
In contrast the growth fraction
represents less than 5% of cells
in a carcinoma of the colon
and this explains its
resistance to chemotherapy.

9. However, metastases from
colonic carcinoma, deposited in
the liver and elsewhere initially,
have a high growth fraction and
are sensitive to chemotherapy,
which is frequently given
following surgical removal
of primary tumor.

10. Different forms of cancer differ
in their sensitivity to chemothe-
rapy. The most responsive are
rapidly proliferating tumors:
• lymphomas
• leukemias
• choriocarcinoma
• testicular carcinoma

11. Solid tumors show
a poor response:
• colorectal carcinomas
• adrenocortical carcinomas
• squamous cell
bronchial
carcinomas

12. An intermediate response
is shown by other cancers:
• bladder
• head and neck
• oаt cell bronchogenic carcinoma
• sex-related cancers of the breast,
ovary, endometrium, prostate

13. Solid tumors –Solid tumors –
surgery or irradiation,surgery or irradiation,
plusplus CHEMOTHERAPYCHEMOTHERAPY
““Non-solid tumors” –Non-solid tumors” –
CHEMOTHERAPYCHEMOTHERAPY
Metastases –Metastases –
CHEMOTHERAPYCHEMOTHERAPY

14. • Myelotoxicity (reduction of leukocytes
increases susceptibility to infections)
• Hair loss
Adverse effects
Most of the anticancer agents have
a limited selectivity and damage
all dividing cells. As a result
general adverse effects are:

15. • Damage to GI tract
• Impaired wound healing
• Depression of growth
• Nausea and vomiting
• Carcinogenicity (in rare cases)
• Reproductive toxicity (PRC: D/X)
• Kidney damage
• Hepatotoxicity

16. Resistance to cytotoxic drugs
(primary or acquired) in 90% of cases
– mechanisms:
• Increased rate of synthesis of target enzyme
(dihydrofolate reductase and methotrexate)
• Increased repair of DNA (alkylating agents)
• Insufficient activation of prodrug
– cytarabine (does not undergo phosphorylation)
•Multi Drug Resistance – increasing action of
membrane efflux system (P-gp 170 and 190), etc.

17. Strategy to avoid resistance
Use 3 or 4 anticancer drugs
together or in sequence,
e.g. treatment of lymphomas:
•COP treatment (COP – acronym)
– Cyclophosphamide
– Oncovin®
(vincristine)
– Prednisolone

18. • Each drug should be an active anticancer
drug in its own right.
• Each drug should have a different
mechanism of action and target site within
the cancer cell (this will increase efficacy
and will reduce the resistance).
• Each drug should have a different site
for any organ-specific toxicity.
Criteria for selecting combinations

19. The dosageThe dosage of many antineoplastic drugsof many antineoplastic drugs
is carried out according to the body surfaceis carried out according to the body surface
of the patient,of the patient, calculated in square meterscalculated in square meters
(m(m22
)) by means of nomogram accordingby means of nomogram according
body mass in kg and height in cm.body mass in kg and height in cm.
The best treatment regimens are becomeThe best treatment regimens are become
the "the "gold standardgold standard" for treatment of" for treatment of
cancer. They are develop and annuallycancer. They are develop and annually
update by world oncotherapeutic teams.update by world oncotherapeutic teams.

20. Prof. A. Dudov, MD, PhDProf. A. Dudov, MD, PhD
President of BulgarianPresident of Bulgarian
Cancer Scientific SocietyCancer Scientific Society

22. Anticancer (antineoplastic) drugsAnticancer (antineoplastic) drugs
I. Cytotoxic drugs (cytostatics)
- Alkylators
- Antimetabolites
- Plant-derived drugs and their analogs
- Cytotoxic antibiotics
- Platinum coordination complexes
II. Endocrine agents
- Glucocorticoids
- Sex hormones and antihormones

23. III. Target drugs
- Monoclonal antibodies (MAB)
- Protein (tyrosine kinase) inhibitors
- Inhibitors of production of TNF-α
IV. Inhibitors of bone resorption and metastases
V. Immunomodulators
- Cytokines (ILs, IFNs)
- Vaccines
VI. Radiotherapy
VII. Cancer supportive therapies

24. I.I. CYTOTOXIC AGENTSCYTOTOXIC AGENTS
The majority of cytotoxic
agents inhibit the process
of DNA synthesis within
the cancer cells.
Resting cells (those in the Go
phase) are resistant to many
anticancer drugs.

25. PrecursorsPrecursorsPrecursorsPrecursors
PurinePurine PyrimidinePyrimidine
RibonucleotidesRibonucleotides
DeoxiribonucleotidesDeoxiribonucleotides
DNADNA
RNARNA
ProteinsProteins
MethotrexateMethotrexate
MercaptopurineMercaptopurine
AlkylatorsAlkylators
Cis-platinCis-platin
AntibioticsAntibiotics
NitrosoureasNitrosoureas
Mitotic inhibitorsMitotic inhibitors
AsparagineAsparagine
AsparaginaseAsparaginase

26. Action of cytotoxic agents
on the cell cycle
Cycle non-specific
Alkylators
Antibiotics
Phase specific
Antimetabolites
Mitotic inhibitors

27.  Alkylating agents
These drugs were developed from the
sulfur mustard gases used in the 1st
WW
trenches and which caused bone
marrow suppression in addition to
respiratory toxicity.
Replacement of the sulfur atom by
nitrogen allowed the first alkylating
agents to be obtained.

28. The important functional group is
the di-(2-chlor-ethyl)-amine side chain:
R—NN
CHCH22CHCH22ClCl
CHCH22CHCH22ClCl
The dichlorethylamine chainsdichlorethylamine chains are highly
reactive and produce alkylating groupsproduce alkylating groups
which bind covalentlycovalently to sites within the
DNA such as N7 of guanineN7 of guanine.

30. Chlorambucil
Cyclophosphamide
a) First
alky-
lators
are
di-(2-chlor
ethyl)-
amines:
Nitrogen
mustards

31. •Cyclophosphamide and Chlorambucil
are commonly used for Hodgkin’s
and non-Hodgkin’s lymphoma, chronic
lymphocytic leukemia.
Cyclophosphamide is also used for
immunosuppression in non-malignant
disorders (severe rheumatoid disorders,
myasthenia gravis, multiple sclerosis).

32. Cyclophosphamide is a prodrug.
One of its metabolites is acroleinacrolein.
Acrolein causes bladderbladder toxicitytoxicity
with haemorrhagic cystitis which
can be prevented by prior treatment
with Mesna.
Bladder cancer may
develop years after
cyclophosphamide chemotherapy.
CancerCancer

33. b) Nitrosoureas (the other alky-
lators) inhibit the synthesis of
DNA, RNA, and proteins.
Carmustine crosses BBB.
It is used for brain tumors.
Carmustine and
Lomustine are
used for the treatment of
Hodgkin’s lymphoma.

34. A number of useful chemothera-
peutic agents have been produced by
simple modifications to the
structures of normal purine and
pyrimidine bases.
 Antimetabolites –
produce lethal synthesis

35. • 5-Fluorouracil (5-FU®
: i.v.) – used for the treatment of
carcinoma of stomach, colon, rectum, breast, and pancreas.
• Xeloda®
(p.o.) – used in colorectal carcinoma.
It is a prodrug of 5-FU with very high selectivity.
• Cytarabine: used in acute myeloid leukemias
(It acts after phosphorylation)
a) Analogues of pyrimidine
5-FU

36. 5-FU blocks thymidilate synthase

37. b) Analogues of purine
•Mercaptopurine (6-MP) and
Thioguanine (6-TG): used inused in
childhood acute leukemiachildhood acute leukemia; Fludarabine
•Gemcitabine
is an analogue of pyrimidine too.
It inhibits DNA polymerase and impairs
DNA synthesis. It is used in various carcinomas:
non-small cell lung cancer, pancreatic cancer,
bladder cancers, breast cancer.

38. c) Folic acid antagonists
•Methotrexate, Pemetrexed, Ralitrexed
Folic acid in its reduced form (THF –
tetrahydrofolic acid) is essential for syn-
thesis of the purine ring system. During
these reactions THF is oxidized to dihydro-
folic acid which has to be reduced by
dihydrofolate reductase. Methotrexate
inhibits dihydrofolate reductase and
blocks purine and thymidine synthesis.

39. CN
OH
CH
COOH
CH2
CH2
COOH
N C
H
NH2
H2 N
N
N
N
OH
Folic acid
Methotrexate
H2
CN
OH
CH
COOH
CH2
CH2
COOH
N C
CH3
NH2
N
N
N
N
NH2
(It has immunosuppressive activity too.)

40. Methotrexate is given
for the treatment of:
•acute lymphoblastic leukemia
•non-Hodgkin’s lymphomas
•chorionepithelioma
•non-malignant disorders
(such as psoriasispsoriasis).

41. Adverse effects of methotrexateAdverse effects of methotrexate
•Vasculitis
•Arachnoiditis
•Pharyngitis, pneumonitis
•Cystitis
•Vomiting
•Hepatotoxicity
•Renal dysfunction
PRC: DPRC: D

42.  Plant-derived drugs and their analogs
•Vinca alkaloids
•Derivatives of Podophyllotoxin
•Taxans etc.
They have cycle and phase
specific action on
the cell division.

43. Vinca alkaloids are complex
natural chemicals isolated from
the periwinkle plant (Vinca rosea).
•Vinblastine
•Vincristine
•Vinorelbine (Navelbine®
)
They bind to tubulin and produce
metaphase arrest.
They are used in acute leukemia.

44. (mitotic inhibitors)

45. Podophyllum peltatumPodophyllum peltatum
(May apple)(May apple)
PodophyllotoxinPodophyllotoxin
EpipodophyllotoxinEpipodophyllotoxin
EtoposideEtoposide
TeniposideTeniposide
Derivatives of PodophyllotoxinDerivatives of Podophyllotoxin
(epipodophyllotoxins)(epipodophyllotoxins)

46. Etoposide
•Inhibits mitosisInhibits mitosis
•Acts in late S- or early G2-phases
•Used in treatment of lymphoma;
lung, testicular,
bladder and
prostate
cancer

47. Taxans
•Docetaxel –
in breast cancer
•Paclitaxel
Inhibit the
depolymerization
of tubulin and
block mitosis.
(Taxus brevifolia)

48. a) Anthracyclines
•Daunorubicin
– in advanced HIV-associated
Kaposi’s sarcoma
•Doxorubicin (Adriamycin®
)
– possesses myelosuppression and
dose-related irreversible myocardial
damage due to free radical attack
•Epirubicin, Idarubicin
 Cytotoxic antibiotics
(inhibit DNA replication)

49. Daunorubicin
Idarubicin
Doxorubicin
Epirubicin

50. Mitomycin C
– in cancer of the
bladder (locally after TUR)
•Other antibiotics
Bleomycin in:
– testicular cancer
– melanomasmelanomas, sarcomas
– squamous cell carcinomas

51. Cis-platin binds to DNA and proteins.
It has made a significant impact on the
treatment of testicular teratoma and
ovarian tumors. It has a long t1/2 (72 h)
due to extensive protein binding and
slow renal elimination.
•Renal toxicity is a major
problem. Severe nausea
and vomiting are often
troublesome too. PRC: D.
 Platinum coordination complexes

52. II. Endocrine agentsII. Endocrine agents
Some cancer arise from cell lines with
steroid receptors. Steroid hormones
cause remissions in certain types of
cancer. They usually do not eradicate
the disease, but can alleviate
symptoms for a long period and
do not depress the bone marrow.

53.  Glucocorticoids
suppress lymphocyte mitosis
and are used in combination with
cytotoxic agents in treating of
lymphomas, myeloma
and to induce
a remission in
acute lymphoblasticacute lymphoblastic
leukemialeukemia.

54. •Hydrocortisone, Prednisone
•Dexamethasone, Prednisolone
Glucocorticoids
are also helpful in
reducing oedema around a tumor.
They have antiemetic activity too.

55.  Estrogens
suppress prostate cancer
both locally and metastases, and
provide symptomatic improvement.
GynecomastiaGynecomastia is a common
side effect.
• Ethinylestradiol
• Polyestradiol
phosphate

56.  Progestagens
suppress
endometrial cancer cells
and lung secondaries:
• Gestonorone
• Medroxyprogesterone

57.  Androgens
are used rarely
in the treatment
of carcinoma
ovarii and uteri
•Testosterone
Side anabolicSide anabolic
effect:effect:

58.  Androgen antagonists
suppress prostate cancer cells.
Unwanted effects include:
gynecomastia, decreased
spermatogenesis, decreased libido.
• Bicalutamide, Cyproterone, Flutamide
1 2 3
PSA >> 5

59. Cyproterone (Androcur®
)
p.o. i.m.
– anti-aphrodisiac too.

60.  Inhibitors of alpha-reductase
• Alpha-reductase converts
testosterone in more active
dihydrotestosterone.
• Finasteride is useful orally in the
treatment of benign prostatatic
hyperplasia.

61.  Estrogen antagonists
•Fluvestrant, Toremifen
•Tamoxifen (p.o.) suppresses breast
cancer cells. The trans isomer of Tamoxifen
blocks competitively estrogen receptors.
Adverse effects include
hot flushes and amenorrhoea
in premenopausal women
and vaginal bleeding in
postmenopausal women.

62.  Aromatase inhibitors
• Aminoglutethimide
• Exemestane (Aromasin®
)
• Formestane, Letrozole
- They inhibit aromatase and block conversion
of androgens to estrogens.
- Inhibition of aromatase reduces estrogen
production in adipose tissue, skin, muscle,
and liver of postmenopausal women
(because ovarian aromatase is resistant
to such inhibition!).

63. Aromatase is also presented in the cells of
two-thirds of breast carcinomas and about
80% of these tumors are estrogen-
dependent. Aromatase inhibitors are used
in postmenopausal women with
advanced breast carcinoma.
Side effects include symptoms of estrogen
withdrawal, e.g. headache, hot flushes,
and lethargy; dyspepsia, nausea, alopecia,
skin rash, hypotension, tachycardia.

64. Breast cancer

65. Treatment with the aromatase inhibitor letrozole
reduces the occurrence of distant metastases in Ca mammae

66.  Gonadotrophin releasing
hormone agonists (GnRHAs)
Continuous daily administration
of GnRHAs results in suppression
of testicular and ovarian steroido-
genesis due to decreased levels of
LH and FSH with subsequent
decrease in testosterone (in man)
or estrogens (in women).

67. Gonadotrophin releasing
hormone agonists:
•Leuprolide (Leuproreline)
•GoserelinGoserelin (ZoladexZoladex®®
)) –
3.6 mg/30 days s.c. in:
– palliative treatment of advanced
prostatic carcinoma
– endometriosis

68. III. Target drugs
They block receptors of the growth
and other angiogenic factors:
VEGF – vascular endothelial growth factor
EGF – epidermal growth factor
PDGF – platelet-derived growth factor
PlGF – placental transfer growth factor
TNF-α – tumor-necrosis factor alfa, etc.

69. a) Monoclonal AntiBody (MAB)
•BEVACIZUMAB (AvastinAvastin®®
) – anti-VEGF agentanti-VEGF agent
blocks angiogenesis and the growth of new blood
vessels. It is used to treat various cancers,
including colorectalcolorectal, lung, and kidney cancer, etc.
AvastinAvastin®®

70. Cetuximab
(–)

71. Colorectal cancerColorectal cancer

72. •TRASTUZUMAB (Herceptin®
) is part of a treatment
plan for the adjuvant treatment of patients with HER2
overexpressing, node-positive HER2+ breast cancer.
•CETUXIMAB (an inhibitor of EGF receptor):
used in metastatic colorectal cancer.
www.breastcancer.org/symptoms

73. b) Protein kinase inhibitors
•Imatinib (GlivecGlivec®®
):
used for the oral treatment of chronic myelogenous leukemia
•Everolimus (AfinitorAfinitor®®
) – mTOR inhibitor:
mammalian Target Of Rapamycin) is used: in renal cancer, pancreaticpancreatic
neuroendocrine tumorsneuroendocrine tumors, as an immunosuppressantimmunosuppressant to prevent
rejection of organ transpalntants (including in drug-eluting coronarydrug-eluting coronary
stentsstents to prevent restenosis).
•Lapatinib, Pasopanib
•Sorefenib (used in renal and liver cancer)

74. c) Inhibitors of the production
of TNF-α:
Thalidomide and analogs
- in with Kaposi's sarcomaKaposi's sarcoma, glioblastoma,
multiple myeloma, erythema nodosum
leprosum)

75. IV. Inhibitors of bone resorption and metastases

76. The immune systemimmune system probably
contributes to the final removal
of residual malignant cells, and
most cytotoxic anticancer agentscytotoxic anticancer agents
compromise immune responsivenesscompromise immune responsiveness.
V. IMMUNOMODIFICATORSV. IMMUNOMODIFICATORS

77.  Cytokines –
peptide regulators of inflam-
matory and immune reactions.
•Interleukins, interferons,
colony-stimulating factors,
tumour necrosis factors.

78. IL-2 produced
by T-lymphocytes
which activate
cytotoxic killer
cells. It is received
by recombinant
DNA technology. IL-2 has been
given by i.v. infusion in patients with
metastatic renal carcinoma. IL-2 causesIL-2 causes
many ADRs.many ADRs.

79. Interferon alfa-2b (Intron®
A) – in:
•chronic hepatitis, hairy cell leukemia
• AIDS-related Kaposi’s sarcomaAIDS-related Kaposi’s sarcoma
•renal carcinoma
Interferons (alpha, beta, gamma)
are glycoproteins produced as part
of the natural host defenses to virus
infections. They have antiviral
activity, immunoregulatory function,
reduce multiplication of cancer cells.

80. Papular cutaneous Kaposi’s sarcomaPapular cutaneous Kaposi’s sarcoma
Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8.Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8.

81.  Vaccines
•BCG Immunotherapeuticum –
locally in bladder cancer
after TUR
•Silgard®
and Cervarix®
are vaccines against
certain types of cancer-
causing human papillomavirus
(HPV – type 6, 11, 16, and 18)
CancerCancer

82. Cancer of the cervix uteri
H
P
V
Normal Early Stage
IB
Late Stage
IB
Stage
IB

83. HPVHPV vaccines:vaccines:
SILGARDSILGARD®®
::
0, 2, and 6 month i.m.0, 2, and 6 month i.m.
(from 9 to 26 years old)(from 9 to 26 years old)
CERVARIXCERVARIX®®
CervarixCervarix®®
HPVHPV

84. Prof. G. Gorchev, MD, DSc: Medical University – PlevenMedical University – Pleven

86.  Radio-pharmaceuticals (radionuclides)
- Irradiated with beta-rays):
131
I, 32
P (Sodium phosphate),
183
Pal - palladium, 145
Sm - samarium
89
Sr (strontium)
 Brahiterpiya
(locally in prostate or vaginal cancer)
 Photodynamic cancer therapy
(irradiation with laser light, with consequent
formation of free radicals):
- Porfimer, Temoporfin
VI. Radiotherapy

87. VII. CANCER SUPPORTIVEVII. CANCER SUPPORTIVE
THERAPIESTHERAPIES

88. Analgesics inAnalgesics in
chronicchronic tumourtumour painpain
according to WHOaccording to WHO
11stst
step (weak pain):step (weak pain): Paracetamol (Acetaminophen)
or NSAIDs
22ndnd
step (moderate pain):step (moderate pain): weak opioids (e.g.
Codeine, Dihydrocodeine, Oxycodone,
Propoxiphen, Tramadol) ± Paracetamol or NSAIDs
33thth
step (step (siveresivere pain):pain): strong opioids (e.g. Fentanyl
– Durogesic® TTS, Morphine or Pethidine) ±
Paracetamol or NSAIDs

90. Cisplatin
Carmustine
Cyclophosphamide
Mitomycin C
L-Asparginase
Fluorouracil
Methotrexate
Etoposide
Vincristine
Emetogenic activity
5-HT3-blockers
D2-blockers
Glucocorticoids
H1-blockers
Antiemetic activity

91. Colony-stimulating
factors (CSFs)
•are used in special cancer
therapy centers to reduce the
severity and duration of
neutropenia induced by cytotoxic
anticancer chemotherapy;
•used in aplastic anaemia;
•used in anaemia in AIDS too.

92. Molgramostim
(Recombinant Human
Granulocyte-Macrophage
Colony-Stimulating Factor – rHuGM-CSF)
Filgrastim
(Recombinant Human
Granulocyte Colony-
Stimulating Factor –
rHuG-CSF)

94. ““BURNOUTBURNOUT” syndrome” syndrome

95. www.medpharm-sofia.eu