Cancer Chemotherapy (Cytostatics)

C A N C ER C H EM O TH ER A P Y
(C Y TO S TATIC S )
dr. Agung Nova Mahendra, S.Ked., M.Sc.
Department of Pharmacology & Therapy

Faculty of Medicine, Udayana University
Cancer Characteristics
Introduction
Challenges in Cancer Chemotherapy:

High cure rates vs. High mortality rates
Benefit vs. Risk
Specific & targeted therapy
Many cancers develop P-gp overexpression
(increased drug efflux)
Goal: developing cancer cells-specific drugs

using the advances in cell & molecular
biology
P-glycoprotein
Comprehension of cell cycle kinetics
is a must!
Two (2) determinants of the

anticancer drugs action & clinical
uses:
Cancer cell population kinetics
Cancer cell cycle
Classification
ANTICANCERS
ANTICANCERS
Mitotic
Mitotic spindle
spindle Hormonal
Hormonal
Action
Action on
on DNA
DNA inhibition
inhibition agents
agents
Damage DNA: Inhibit synthesis Microtubule 1. Agonists

1. Alkylation or functions: inhibitors (Prednisone)
(Cyclophosphamide) 1. Antimetabolites (Vincristine) 2. Antagonists
(Methotrexate) (Tamoxifen)
2. Free radical
Formation 2. Topoisomerase
(Doxorubicin) inhibitors
(Etoposide)
Classifi
cation Based on Cancer Cell
Cycle Kinetics
Anticancers act specifically on
cycling tumor cells Cell cycle-
specific (CCS) drugs Effective
when large proportion of tumor cells
are proliferating
Ex: Bleomycin, Vinca alkaloids
Anticancers act on both cycling &
resting tumor cells Cell cycle-non-
specific (CCNS) drugs
Ex: Alkylating agents
CellCycle Kinetics
Vinca alkaloids
Bleomycin
Antimetabolites
The Log-KillH ypothesis
Cytostatics kill tumor cells with 1st

order kinetics given dose kills
same proportion instead of same
number of tumor cells
R esistance M echanism s to A nticancers
Mechanisms Drug examples

Increased DNA repair Most alkylating agents &
Cisplatin
Formation of trapping Bleomycin , Cisplatin, &
agents Anthracyclines
Changes in target Methotrexate
enzymes
Decreased activation of Purine antimetabolites
prodrugs (Mercaptopurine &
Thioguanine) & Pyrimidine
antimetabolites (Cytarabine
& Fluorouracil)
Inactivation of Most of Purine & Pyrimidine
anticancers antimetabolites
Decreased drug Many anticancers
A LK YLATIN G A G EN TS
They are CCNS drugs

Examples:
Nitrogen mustards: chlorambucil,
cyclophosphamide, mechlorethamine
Nitrosoureas: carmustine, lomustine
Alkylsulfonates: busulfan & derivative
Others: Cisplatin, Carboplatin,
Dacarbazine, & Prodacarbazine
General pharmacodynamics (PD):
Form reactive molecular species that alkylate
nucleophilic groups on DNA bases (particularly
the N-7 position of guanine) base cross
linking, abn base pairing, & DNA Strand
Breakage
(DNA SB).
Resistance mechanisms:
increased repair, decreased permeability, &
formation of trapping agent (thiols)
ALKYLATIN G AG EN TS
A. Cyclophospamide
Pharmacokinetics (PK): biotransformed by
CYP450. Clinically important breakdown
product is Acrolein hemorrhagic cystitis
Use: non-Hodgkins lymphoma, breast &

ovarian cancers, & neuroblastoma
Toxicity: GI distress, myelosuppression,

alopecia, cardiac dysfunction, pulmo. Toxicity,
SIADH, & hemorrhagic cystitis tx: mesna
B. Mechlorethamine
PK: spontaneous conversion into
reactive metabolite
Use: Hodgkins lymphoma
Toxicity: similar with
cyclophosphamide + sterility, &
marked vesicant effect.
C. Cisplatin & Carboplatin

PD: DNA strands cross-linking
PK: IV
Use: testicular carcinoma, bladder,
lung, & ovarian cancers
CISPLATIN CARBOPLATIN
GI distress Less neurotoxic
Mild hematotoxic Less nephrotoxic
Neurotoxic (PN & CN Myelosuppression >>
VII damage)
Nephrotoxic
D. Procarbazine
PD: forms H2O2 free radical genesis
DNA strand scission
PK: PO; CSF distribution
Use: Hodgkins lymphoma
neurotoxic
Inhibits many enzymes, including MAO
Leukemogenic
E. Others:
1. Busulfan: CML
2. Carmustine & Lomustine: brain
tumors
3. Dacarbazine: Hodgkins lymphoma
AN TIM ETABO LITES
A. Methotrexate
PD: substrate & inhibitor of DHFR
reduced thymidylate, purine
nucleotides, & amino acids synthesis.
Polyglutamate derivatives is important
for cytotoxicity
PK: PO & IV; poor CNS distribution; May

crystallized in renal tubules
Use: choriocarcinoma, cutaneous T cell

lymphoma, breast cancer, RA, psoriasis,
Toxicity: myelosuppression,
mucositis. Long term use:
hepatotoxicity, pulmonary infiltrates.
Leucovorin rescue
Interaction: Salicylates,
sulfonamides, sulfonylureas, NSAIDs
enhanced toxicity
AN TIM ETABO LITES
B. Mercaptopurine (6-MP) & Thioguanine

(6-TG)
PD: purine antimetabolites activated
by HGPRTases
PK: Metabolism by xanthine oxidase
Use: Acute leukemias, CML
Toxicity: myelosuppression & hepatic
dysfunction
Interaction: Allopurinol
AN TIM ETABO LITES
C. Cytarabine (Ara-C or Cytosine arabinoside)

PD: pyrimidine antimetabolite activated by
kinases to AraCTP (DNA polymerase
inhibitor).
Most specific antimetabolites on S-phase
PD: IV
Use: acute leukemias
Toxicity: GI distress, myelosuppression, &
neurotoxicity (cerebellar dysfunction &
peripheral neuritis)
AN TIM ETABO LITES
D. Fluorouracil (5-FU)
PD: converted to 5-FdUMP inhibits
thymidylate synthase thymineless
death
PD: IV
Use: bladder, breast, colon, head & neck,
liver & ovarian cancers
Topical use: keratoses & superficial BCC
Toxicity: GI distress, myelosuppression, &
alopecia
PLAN T ALKALO ID S
A. Vinblastine & Vincristine
PD: prevent tubulin dimers assembly to
microtubule (MT); CCS (M phase)
PK: IV; good distribution (exc. CSF)
Uses: Vinblastine acute leukemias,
lymphomas, Wilms tumor, &
choriocarcinoma; Vincristine:
lymphomas, neuroblastoma, testicular
carcinoma, & Kaposis
Vinblastine sarcoma
Vincristine
GI distress No serious
Myelosuppression myelosuppression
Neurotoxic
(areflexia, PN,
paralytic ileus)
PLAN T ALKALO ID S
B. Etoposide & Teniposide
PD: Top2 inhibitor & mitochondrial
electron transport inhibitor.
PK: PO
Uses: SCLC, prostate & testicular
carcinoma
& alopecia
PLAN T ALKALO ID S
C. Paclitaxel & Docetaxel
PD: inhibits disassembly of MT into
tubulin monomers.
PK: IV
Uses: advanced breast & ovarian ca
Toxicity:
Paclitaxel: neutropenia, thrombocytopenia,
PN (>>)
Docetaxel: myelosuppression
AN TIBIO TICS
Bhattacharya & Mukherjee (2015)

AN TIBIO TICS
A. Doxorubicin & Daunorubicin

PD: Top2 inhibitors, base pair
intercalation, free radicals formation,
membrane disruption
CCNS
PK: IV; red urine color
Use: Dox Hodgkins lymphoma, breast,
thyroid ca, etc. Dauno acute leukemias
Toxicity: cardiotoxicity (ion-mediated free
radical formation)
AN TIBIO TICS
B. Bleomycin
PD: Glycopeptide antibiotics generates
free radical binds DNA DNA SB DNA
synthsis inhibition
CCS (G2 phase)
PK: IV; inactivated by tissue aminopeptidases
Use: Hodgkins lymphoma, testicular ca, SCC
Toxicity: pulmonary dysfunction
(pneumonitis, fibrosis), hypersensitivity,
mucocutaneous reactions
H O RM O N AL AN TICAN CERS
A.Glucocorticoid
PD: reduces tumor-induced
inflammation & pain; reduces
androstenedione &/ DHEA synthesis
by adrenal glands (Dorff, 2012)
Use: Leukemias & lymphomas
B.Sex Hormone Antagonists

Tamoxifene, Toremifene: SERM
Use: breast ca
Toxicity: vaginal bleeding, venous
thrombosis, hot flushes
Flutamide: androgen receptor antagonist
Use: prostatic ca
Toxicity: gynecomastia, hepatic
dysfunction, hot flushes
C.GnRH Analogs
Leuprolide, Goserelin, & Nafarelin
PD: inhibit release of LH & FSH
Use: prostatic ca
Toxicity: bone pain, hematuria,
gynecomastia, testicular atrophy,
impotence
D.Aromatase Inhibitors
Anastrozole, & Letrozole
PD: inhibit conversion of
androstenedione to estrone by
aromatase
Use: advanced breast ca
Toxicity: back & bone pain, dyspnea,
peripheral edema
M ISCELLAN EO U S
AN TICAN CERS
Asparaginase depletes asparagine
Imatinib act on Bcr-Abl oncogene (in

Philadelphia chromosome) CML
Interferons antineoplastic,
immunosuppressive, & antiviral
Monoclonal antibodies: Trastuzumab

monoclonal Ab on surface protein of breast
cancer cells overexpressing HER2
Philadelphia Chrom osom e
Principles ofCom bination Chem otherapy
Active per se
Different PD
Different toxicity
Minimal cross
resistance
AdditionalStrategies
Leucovorin
Mesna
Dexrazoxane
AN TICAN CERS D EVELO PM EN T
D eep sea-derived potentialanticancers
Russo et al. (2015)

G atastatin inhibits -tubulin-facilitated
M T nucleation in centrosom e ofH e-La
cells
Normal
bipolar Abnormal
spindle bipolar &
short
spindle
Chinen et al. (2015) GSLES, University of

Chromosomes Tsukuba,
1-1-1 Tennodai, Tsukuba, Japan
REIC*:N ovelanticancer m odality
Hiroshi Kumon, MD, PhD (Department of Urology,

GSMDPS, Okayama University, Shikata-cho, Okayama-
shi, Okayama, Japan)
*REIC (Reduced Expression in Immortalized Cells): was

TER IM A K A SIH
M ATU R SU K SM A
M ATU R N U W U N
TH A N K YO U
A R IG ATO U
G O ZA IM A SU

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C A N C ER C H EM O TH ER A P Y

dr. Agung Nova Mahendra, S.Ked., M.Sc.

Department of Pharmacology & Therapy

Challenges in Cancer Chemotherapy:

Goal: developing cancer cells-specific drugs

Two (2) determinants of the

Damage DNA: Inhibit synthesis Microtubule 1. Agonists

Cytostatics kill tumor cells with 1st

Mechanisms Drug examples

They are CCNS drugs

Use: non-Hodgkins lymphoma, breast &

Toxicity: GI distress, myelosuppression,

C. Cisplatin & Carboplatin

PK: PO & IV; poor CNS distribution; May

Use: choriocarcinoma, cutaneous T cell

B. Mercaptopurine (6-MP) & Thioguanine

C. Cytarabine (Ara-C or Cytosine arabinoside)

Bhattacharya & Mukherjee (2015)

A. Doxorubicin & Daunorubicin

B.Sex Hormone Antagonists

Imatinib act on Bcr-Abl oncogene (in

Monoclonal antibodies: Trastuzumab

Russo et al. (2015)

Chinen et al. (2015) GSLES, University of

Hiroshi Kumon, MD, PhD (Department of Urology,

*REIC (Reduced Expression in Immortalized Cells): was

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