CANCER CHEMOTHERAPY

FRANCIS RAYMOND M. CASTOR, M.D.

F.P.C.S.
DEPARTMENT OF PARMACOLOGY

CANCER
Cellular disease
Shift in the control mechanism that controls
proliferation
Neoplastic transformation
Express surface antigens of the normal fetal
type
Immaturity, chromosomal abnormalities

Excessive proliferation = Tumors

Invade or compress other structures
Tumor stem cells
Can express colony forming capabilities
Invasion and metastases cause death

CAUSES OF CANCER
Environmental exposure to chemical
carcinogens
Herpes/ papilloma group DNA viruses/ type C
RNA viruses
Cellular genes/ oncogene/ deleted or
damaged tumor suppressor genes

THERAPEUTIC MODALITIES
Reduction of tumor burden by
Radiation
Surgery
Chemotherapy
Killing 99.99% of colonogenic tumor cells will
result in remission of neoplasm= symptomatic
improvement

THE IDEAL ANTI CANCER DRUG

Eradication of tumor cells without damage to
normal cells
No drugs meets this criterion

BASIC PHARMACOLOGY

Polyfunctional alkylating agents

Antimetabolites
Plant alkaloids
Antitumor antibiotics
Hormonal agents
Miscellaneous anticancer agents
Anti VEGF agents

POLYFUNCTIONAL ALKYLATING
AGENTS
Contains ethylene amines or a nitrosourea
moiety
Cytotoxic effects via transfer of alkyl groups to
various cellular constituents.
Lysine carbamoylation via isocyanate
formation in nitrosoureas
Major site is N7 position of guanine in DNA /
N1, N3 of adenine, N3 of cytosine, O6 of
guanine

Chlorambucil, Mechlorethamine
Cyclophosphamide
Melphalan
Thiotepa
Busulfan
Carmustine/ lomustine
Altretamine
Procarbazine
Cisplatin, carboplatin, oxaliplatin

 Resistance: increased capability of cells to

repair DNA lesions, decrease permeability to
the drug and increased GSH formation
Increased GSH production inactivates the
alkylating agent via conjugation
(
catalysed by S-transferase )

 Has direct vesicant effects and can damage

tissues at the injection site/ systemic toxicity.
Toxicity is generally dose related
Produces nausea and vomiting 30-60 mins. of
administration, relieved by pre- treatment
with a SSRI Ondansetron or Granisetron

Major toxicities
Moderate depression of peripheral blood
count ( indication for adequate absorption)
Excessive doses: bone marrow depression
Alopecia , hemorrhagic cystitis
Nephrotoxicity, peripheral sensory neuropathy
Hepatic dysfunction

Nitrosoureas
Non cross resistant with other alkylating
agents
Highly lipid soluble and crosses the blood
brain barrier, useful for CNS tumors
More effective in the plateau phase than in
exponentially growing cells
Streptozocin: Insulin secreting cell carcinoma
of the pancreas

Drugs probably acting as alkylating

agents
Procarbazine: Hodgkins disease / non
Hodgkin s lymphoma
Produces chromosome breaks, prolongs
interphase
Increased risk of secondary cancers : leukemia
Carcinogenic potential is higher

 Dacarbazine: melanoma, Hodgkins and soft

tissue sarcomas
Altretamine: ovarian CA who have progressed
despite treatment with an alkylating agent
and a platinum based drug/ neurotoxicity,
somnolence, mood changes, peripheral
neuropathy

Cisplatin / carboplatin / Oxaliplatin: Platinum

analogs, complexes and synergizes with other
drugs
Broad range of solid tumors, Non small cell Lung
CA, Esophageal CA, Gastric CA, GU and head
and neck CA.
Neurotoxicity limits dose: peripheral sensory
neuropathy worsened upon exposure to cold (
Oxaliplatin) cumulative but reversible

Antimetabolites (structural analogs)

Acts on the intermediary metabolism of
proliferating cells
Includes
Methotrexate
Purine antagonists
Mercaptopurine, Fludarabine, Cladribine

Pyrimidine antagonists
5 FU, Capecitabine, Cytarabine, Gemcitabine

Methotrexate
Folate antagonists via DHFR
Interrupts synthesis of thymidilate, purine
nucleotides, serine and methionine
Polyglutamate derivatives of MTX are retained
in CA cells
Inc. inhibitory action on folate enzymes

 Resistance to MTX due to

Decreased drug transport
Decreased polyglutamate formation
Increased DHFR synthesis via gene amplification
Altered DHFR with reduced MTX affinity
Decreased drug accumulation via multidrug
resistant P170 glycoprotein transporter

 Administered
IV
Intrathecal
Oral: 90% of dose excreted in urine within 12
hours
The drug is not subject to metabolism
Serum levels are proportionate to dose as long as
renal function and hydration is adequate
Effects of MTX are reversed by Leucovorin
( rescue drug for overdosage)

Purine anragonists
Mercaptopurine
Used primarily for the treatment of acute
childhood leukemia
Azathioprine, an analog is an
immunosuppressive agent
Synergystic with cytarabine

 Resistance occurs most common by decrease

in HGPRT activity or elevated levels of alkyl
phosphatase
Simultaneous therapy with allopurinol results
in excessive toxicity unless the dose of
Mercaptopurine is reduced to 25%

Fludarabine
Low grade non Hodgkins lymphoma and
Chronic lymphocytic leukemia
Given parenterally
Dose limiting toxicity is myelosuppression

Cladribine
Hairy cell leukemia, CLL, NHL
Single 7 day infusion
Immunosuppressive with decreased CD4 and
CD8 lasting over 1 year

Pyrimidine antagonists
5 FU: inhibition of DNA synthesis through
thymineless death
Normally given per IV due to erratic
bioavailability via oral route ( high levels of
breakdown enzyme in the gut)
Widely used in colorectal CA

Cytarabine
S phase specific antimetabolite
Highly schedule dependent must be given via
continuous IV infusion q 8-12 hours for 5-7
days
Myelogenous leukemia

Plant Alkaloids

Vinblastine
Depolymerization of microtubules
Mitotic arrest at metaphase
Hodgkins lymphoma, non Hodgkins
lymphoma, Breast CA
Vinblastine: multiple myeloma,
Rhabdomyosarcoma, Neuroblastoma, Ewings
sarcoma, Wilms tumor

Epidophyllotoxins
Etoposide and Teniposide
Block cell division at S-G 2 phase of cell cycle
Etoposide: germ cell CA, small cell CA, non
small cell lung CA, gastric CA, Hodgkins/ NHL
Teniposide: ALL

Camptothecins
Irinotecan
Secondline monotherapy for metastatic
colorectal CA, who have failed 5 FU/
Leucovorin

Taxanes
Paclitaxel
Microspindle poison
Cas: ovarian, breast, non small cell, bladder,
Kaposis sarcoma
Docetaxel: advanced breast CA, small cell Lung
CA, ovarian, Bladder CA, Head and neck CA

Antitumor antibiotics
Doxorubicin/ daunorubicin : solid tumors/
AML
Anthracyclines: cardiotoxic
Used in combination with cyclophosphamide,
cisplatin and 5 FU

Dactinomycin
Inhibits all forms of DNA dependent RNA
synthesis
Wilms tumor, Rhabdomyosarcoma, Ewings
sarcoma
Radiation recall reaction

Mitomycin C
Squamous cell CA of the anus with 5 FU
Intravesical treatment for superficial bladder
CA
Non absorbed systemically via this route
No systemic toxicity for intravesical treatment
Common toxicities are hemolytic uremic
syndrome, hemolytic anemia,
thrombocytopoenia, renal failure, interstitial
pneumonitis

Hormonal agents
Estrogen and Androgen inhibitors
Tamoxifen
Flutamide
Bicalutamide

Gonadotropin releasing hormone agonists

Leuprolide
Goserelin

Aromatase inhibitors
Aminogluthetimide
Letrozole
Exemestane

Tamoxifen

Early and metastatic breast CA

Chemopreventive for high risk patients
Competitive agonist inhibitor of estrogen
Estrogen sensitive tumors

Flutamide / Bicalutamide
Used in combination with RT for treatment of
Prostate CA, early an metastatic

Leuprolide/ Goserelin
Analogs of GnRH
When given in depot, these lead to a transient
release of FSH and LH
Castration levels of testosterone
For prostate CA
Flushes, impotence and gynecomastia

Miscellaneous
Imatinib: tyrosine kinase inhibitor; CML
Asparaginase
Hydroxyurea: CML, blast crisis in AML,
myelosuppression limits the dose
Mitotane: analog of DDT, adrenocortical CA
Bone Marrow growth Factors: Erythropoeitin:
chemotherapy related anemia

Anti VEGF
Cetuximab
Bevacizumab
Inhibits the tyrosine kinase domain of
epidermal growth factor