Transcript Antineoplastic Drugs

Anticancer Drugs
General Pharmacology
M212
Dr. Laila M. Matalqah
Ph.D. Pharmacology
Anticancer Drugs.
 Antineoplastic Drugs = Cytotoxic Drugs = Cancer
chemotherapy.
 Cancer cells
* Uncontrolled proliferation.
*Dedifferentiation & loss of function.
*Invasiveness.
*Metastasis.
 Anticancer drugs available do not specifically
recognize neoplastic cells but, rather, affect all kinds
of proliferating cells, both normal and abnormal
Ideal anti cancer drug–currently not available
Main Approaches to Treat Cancer
• Surgical excision
• Radiation
• Chemotherapy:
i – When the tumor is disseminated and not
amenable to surgery TT.
ii – Or as a supplement to surgery and irradiation to
reduce the number of micrometastasis “adjuvant
TT”
iii – Before surgery to shrink the tumor “neoadjuvant
TT”.
iv – In lower doses to assist in prolonging a
remission “maintenance TT”
Aims of Chemotherapy
Curative: to obtain complete remission as in
Hodgkin’s disease.
2. Palliative: to alleviate symptoms and avoidance
of life-threatening toxicity but with little
expectation of complete remission as in
esophagus Ca-dysphagia.
3. Adjuvant: Chemotherapy is also used as a
supplemental treatment to attack
micrometastases following surgery and radiation
treatment
1.
General ADRs of Anticancer Drugs
• Most of them have a narrow Therapeutic
Index.
1.Nausea & vomiting: common, severe,
prolonged  TT rejection.
Antiemetics are needed.
2.Bone Marrow depression
pancytopenia and immunosupression
(antibody and cell mediated)  infection
“apportunistic” – important dose limiting
factor. Repeated blood count is essential.
blood transfusions may be needed.
ADRs (cont.)
3.Damage to GIT lining & other mucosal
surfaces diarrhea , stomatitis and mouth
ulcer.
4.Hair bulb damage: alopecia – Reversible
in 2-6 months.
5.Delayed wound healing.
6.Effect on germ cells  sterility,
teratogenicity and mutagenicity.
ADRs (cont.)
7.Various organ damage – renal, hepatic,
cardiac ,pulmonary……
8.Secondary cancer ,10 ys or more, mutagenic effect.
9.Hyperuricemia : cell break down  purine uric acid  gout and renal damage
10.Local toxicity due to extravasation
Problems associated with
chemotherapy
1. Resistance
• Inherent resistance – melanoma
• Acquired resistance – after prolonged (suboptimal doses)
low doses.
• Resistance could be minimized by:
 Short term, intensive, intermittent therapy , with drug
combination
2. Toxicity:
• affects normal cells undergoing rapid proliferation (for
example, cells of the buccal mucosa, bone marrow, GI
mucosa, and hair follicles
Combinations of drugs
• Cytotoxic agents with different toxicities, and with
different molecular sites and mechanisms of action,
are usually combined at full doses.
• This results in higher response rates, due to
additive cytotoxic effects and nonoverlapping host
toxicities.

Advantages of drug combinations
 1.Maximum cell kill & tolerated toxicity.
 2.Effective against wide range of cell lines.
 3.Slow or prevent development of resistance
Guidelines when selecting Drug
combination
1.Use drugs that show activity against the
type of tumor being treated.
2.Use drugs that have minimal or no
overlapping toxicities, ADRs of the
drugs should be diverse and not centered
on the same organ system.
3.The dosing schedule for each drug
should be optimal and doses should be
given at constant times.
Guidelines when selecting Drug
combination(cont.)
• 4. Use drug combination that result in
synergistic activity optimizing
therapeutic benefits and reducing ADRs .
• 5. use drugs that have different
mechanisms of action ,or that affect
tumor cells at different stages of the cell
cycle.
Tumor growth rate
• Initially rapid, decreases as tumor size
increases (?)
because of unavailability of nutrients and
oxygen, due to less blood supply.
• Radiation and surgery decrease the size 
adequate blood supply  increase growth
rate  increased susceptibility to
chemotherapy.
Pharmacological guidelines

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e.g. leukemic cells in CNS may be
unaminable for some cytotoxic drugs (?)
can not cross BBB
This problem will be solved by Intrathecal
administration and or irradiation of craniospinal axis.
Similarly, drugs may be unable to
penetrate certain solid tumors.!!!
Classification of Anticancer Drugs
1. Antimetabolites.
2. Alkylating agents.
3. Antibiotics.
4. Mytotic spindle poisons.
5. Hormones.
6. Monoclonal antibodies
Antimetabolites
• Are structurally related to normal cell
components.
• They interfere with the availability of purine
or pyrimidine nucleotide precursors.
By :1. inhibiting their synthesis or
2. competing with them on DNA & RNA
synthesis
Antimetabolites
• Methotrexate (MXT)
•
“Antifolate”, inhibits Dihydrofolate reductase
(DHF) enzyme, decreasing tetrahydrofolate (THF)
production  DNA&RNA
• The inhibition of DHFR can only be reversed by
administration of leucovorin or folinic acid rescue
(FH4).
• USES: acute lymphocytic leukemia (ALL), breast
cancer, choriocarcinoma,, and head and neck
Carcinomas, Severe psoriasis & rheumatoid
arthritis.
Antimetabolites
• Methotrexate (MXT)
ADRs:
• Pulmonary toxicity
• Renal damage: high-dose MTX and its 7-OH
metabolite, which can precipitate in the tubules.
– Alkalinization of the urine and hydration help to prevent
this problem
• Common: stomatitis, myelosuppression, erythema,
rash, urticaria, and alopecia. Some of these
adverse effects can be prevented or reversed by
administering leucovorin
Other Antimetabolites (AM)
• 6-Mercaptopurine (purine AM).
Uses: Acute leukemias,
ADR: Hepatotoxicity
• Cytoarabine (pyrimidine AM).
In: Acute leukemias.
• 5- Flurouracil - (pyrimidine analogue, inhibits
thymidylate synthetase – inhibit DNA synthesis).
Uses: breast cancer, Ovary, skin & GIT carcinoma
Alkylating Agents
• MOA: by covalently binding to nucleophilic
groups on various cell constituents Transferring an alkyl group to DNA in the
N-7 of guanine  breakage of DNA
strand
• and cross linkage of two strands at two
guanines  blockade of DNA synthesis
and tumor cell death.
Alkylating Agents
• Cyclophosphamide
• Inactive, metabolized by hepatic P-450 to:
Phosphoramide (active cytotoxic) and Acrolein
(haemorrhagic cystitis)
• administered by the oral route
• Used in: Lymphomas, Lymphocytic Leukemia, breast &ovary
Ca
• Haemorrhagic cystitis is minimized by:
 high fluid intake

Irrigation of the bladder with N-acetylcysteine
 Adequate hydration as well as IV injection of MESNA
(sodium 2-mercaptoethane sulfonate), which neutralizes the
toxic metabolites (acrolein)
Other Alkylating Agents
Nitrosoureas :Carmustine (IV) &
Lomustine (Orally)
• Cross BBB  in tumor of brain and meninges.
Busulfan: selective on BM
• Uses In: mylogenic leukemia
• ADRs : pulmonary fibrosis
Other Alkylating Agents
Cisplatin:
• MOA: similar to alkylating agent .
In: Ca testes, bladder, lung and ovary.
ADRs: Ototoxicity, hepatoxicity
,nephrotoxicity and neurotoxicity
Cytotoxic Antibiotics
• Produce their effects mainly by direct
action on DNA
1.Doxorubicin and daunorubicin :
MOA: Free radical generator inhibit NA synthesis.
In : Leukemias and lymphomas and other solid tumors.
ADRs: dose-dependent Cardiotoxicity –arrhythmias
&CHF
2. Bleomycin:
Free radical generator.
Uses: squamous cell Carcinoma, lymphoma
ADRs: Pulmonary toxicity (Pulmonary fibrosis and
pneumonia)
Mitotic Spindle Poisons
Vincristine (VX) and Vinblastine (VBL)
• From vinca alkaloids
• MOA: Microtubule inhibitors- Inhibits mitosis at
metaphase by binding to tubulin (M-phase).
• Uses: Acute leukemias, lymphomas, and
sarcomas
ADRs:
• Local tissue damage, Thrombophlebitis and NM
effects as muscle weakness and parasthesia.
Hormones and Hormone
antagonists
1. prednisone reduced to Prednisolone.
Used in lymphomas and leukemias.
2. Estrogens in prostate Ca, Ca breast in
the male.
3. Antiestrogen “Tamoxifen” in Ca breast
in female. (estrogen receptor antagonist)
4. Progestogens in endometrial tumors and
Ca breast and prostate.
5. Androgens in Ca breast.
Monoclonal Antibodies
• Rituximab and Cetuximab
• MOA: binds to cytotoxic B lymphocytes, inducing
complement and antibody dependent, cellmediated cytotoxicity of the B cells.
• It is important to infuse rituximab slowly : can
cause Hypotension, bronchospasm, and
angioedema
• Pretreatment with diphenhydramine,
acetaminophen, and bronchodilators
• Uses: chronic lymphocytic leukemia.