This document discusses anticancer drugs and their mechanisms of action. It notes that anticancer drugs are increasingly important in veterinary practice and are often used in combination with surgery and/or radiotherapy. The document then provides details on the cell cycle, types of anticancer drugs including cytostatics, and their various mechanisms of action such as inhibiting DNA synthesis, disrupting mitosis, and incorporating false building blocks. It also discusses mechanisms of resistance that tumors can develop.

1. Anticancer Drugs
AMIR SOHAIL

2. • The use of antineoplastic drugs is
becoming increasingly important in
veterinary practice.
• These drugs are often used in combination
with surgery and /or radiotherapy.
• Generally ,they are prescribed and
adminsitered in combination drugs having
different mechanisms of action to get
greater tumor cell kill.

3. Cancer
Cancer is a disease of cells characterized by
• Progressive
• Persistent
• Perverted(abnormal)
• Purposeless
• Uncontrolled Profileration of tissues

4. Chemotherapy of Malignant Tumors
• A tumor (neoplasm) consists of cells that
proliferate independently of the body’s
inherent “building plan.”
• A malignant tumor (cancer) is present
when the tumor tissue destructively
invades healthy surrounding tissue or
when dislodged tumor cells form
secondary tumors (metastases) in other
organs.

6. Cell cycle
• Both normal as well as cancerous cells
must pass through phases of cell cycle
• G1 Phase(Presynthetic Phase):synthesis
of enzymes and other cellular components
needed for DNA synthesis
• Synthetic Phase(S phase): DNA synthesis
takes place

7. Cell cycle
• G2 phase (premitotic phase): Synthesis of
cellular components for mitosis (pro-
teins and RNA synthesis).
• M phase: Mitotic cell division takes place.
• Go phase (resting phase): Cells stop
dividing temporarily or permanently.

9. Chemotherapy of Malignant Tumors
• A cure requires the elimination of all
malignant cells (curative therapy). When
this is not possible, attempts can be made
to slow tumor growth and thereby prolong
the patient’s life or improve quality of life
(palliative therapy).

10. Chemotherapy of Malignant Tumors
• Chemotherapy is faced with the problem
that the malignant cells are endogenous
and are not endowed with special
metabolic properties.

11. Cytostatics
• Cytostatic refers to a medicine that
inhibits cell growth.

12. Cytostatics
• are cytotoxic substances that
particularly affect proliferating or dividing
cells. Rapidly dividing malignant cells are
preferentially injured.
• Damage to mitotic processes not only
retards tumor growth but may also initiate
apoptosis (programmed cell death).

13. Cytostatics
• Tissues with a low mitotic rate are largely
unaffected; likewise, most healthy tissues.
This, however, also applies to malignant
tumors consisting of slowly dividing
differentiated cells. Tissues that have a
physiologically high mitotic rate are bound
to be affected by cytostatic therapy.

14. Cytostatics
• Thus, typical adverse effects occur:
Loss of hair results from injury to hair
follicles; gastrointestinal disturbances,such
as diarrhea, from inadequate replacement
of enterocytes
whose life span is limited to a few days;
nausea and vomiting from stimulation of
area postrema chemoreceptors ;and
lowered resistance to infection from
weakening of the immune system .

17. Cytostatics
• In addition, cytostatics cause bone marrow
depression. Resupply of blood cells
depends on the mitotic activity of bone
marrow stem and daughter cells.

18. Cytostatics
• When myeloid proliferation is arrested,the
short-lived granulocytes are the first to be
affected (neutropenia), then blood
platelets (thrombopenia) and, finally, the
more long-lived erythrocytes
(anemia).Infertility is caused by
suppression of spermatogenesis or follicle
maturation.

19. Cytostatics
• Most cytostatics disrupt DNA metabolism.
• This entails the risk of a potential genomic
alteration in healthy cells (mutagenic effect).
Conceivably, the latter accounts for the
occurrence of leukemias several years after
cytostatic therapy (carcinogenic effect).
Furthermore, congenital malformations are to
be expected when cytostatics must be used
during pregnancy (teratogenic effect).
Cytostatics possess different mechanisms of
action.

20. Cytostatics
• Damage to the mitotic spindle (B).
• The contractile proteins of the spindle
apparatus must draw apart the replicated
chromosomes before the cell can divide. This
process is prevented by the so-called spindle
poisons that arrest mitosis at metaphase by
disrupting the assembly of microtubules into
spindle threads.
• The vinca alkaloids, vincristine and
vinblastine (from the periwinkle plant, Vinca
rosea) exert such a cell-cycle-specific effect.

21. Cytostatics
• Paclitaxel, from the bark of the pacific yew
(Taxus brevifolia), stabilizes microtubules
and as a result, interferes with the normal
breakdown of microtubules during cell
division. Docetaxel is a semisynthetic
derivative. Together with docetaxel, it
forms the drug category of the taxanes.

23. (A)Inhibition of DNA and RNA synthesis
• Mitosis is preceded by replication of
chromosomes (DNA synthesis) and
increased protein synthesis (RNA
synthesis). Existing DNA serves as a
template for the synthesis of new DNA or
RNA.

24. De novo synthesis may be inhibited by:
• Damage to the template (1).
• Alkylating cytostatics are reactive
compounds that transfer alkyl residues into
a covalent bond with DNA. For instance,
mechlorethamine (nitrogen mustard) is able
to cross-link double-stranded DNA on giving
off its chlorine atoms. Correct reading of
genetic information is thereby
rendered impossible.

26. • Other alkylating agents are chlorambucil,
melphalan,, cyclophosphamide, ifosfamide,
lomustine, and busulfan.
• Specific adverse reactions include
irreversible pulmonary fibrosis due to
busulfan and hemorrhagic cystitis caused by
the cyclophosphamide metabolite acrolein
(preventable by the uroprotectant mesna).
Cisplatin binds to (but does not alkylate) DNA
strands.

29. • Cystostatic antibiotics insert
themselves into the DNA double strand;
this may lead to strand breakage (e.g.,
with bleomycin). The anthracycline
antibiotics daunorubicin and adriamycin
(doxorubicin) may induce cardiomyopathy.
Bleomycin can also cause pulmonary
fibrosis.

30. • The epipodophyllotoxins, etoposide
and teniposide, interact with
topoisomeraseII, which functions to split,
transpose, and reseal DNA strands ; these
agents cause strand breakage by
inhibiting resealing.

31. (2) Inhibition of nucleobase synthesis
• Tetrahydrofolic acid (THF) is required
for the synthesis of both purine bases and
thymidine. Formation of THF from folic
acid involves dihydrofolate reductase .

32. Inhibition of nucleobase synthesis
• The folate analogues aminopterin and
methotrexate (amethopterin) inhibit
enzyme activity as false substrates. As
cellular stores of THF are depleted,
synthesis of DNA and RNA building blocks
ceases. The effect of these antimetabolites
can be reversed by administration of folinic
acid (5-formyl-THF, leucovorin, citrovorum
factor).

34. (3). Incorporation of false building
blocks
• Unnatural nucleobases (6-mercaptopurine;
5-fluorouracil) or nucleosides with
incorrect sugars (cytarabine) act as
antimetabolites. They inhibit DNA/RNA
synthesis or lead to synthesis of missense
nucleic acids.

36. • 6-Mercaptopurine results from
biotransformation of the inactive precursor
azathioprine .
• The uricostatic allopurinol inhibits the
degradation of 6- mercaptopurine such
that co-administration of the two drugs
permits dose reduction of the latter.

37. • Frequently, the combination of cytostatics
permits an improved therapeutic effect
with fewer adverse reactions.

39. Mechanisms of resistance are
multifactorial
• Initial success can be followed by loss of
effect because of the emergence of
resistant tumor cells.
• Diminished cellular uptake may result from
reduced synthesis of a transport protein
that may be needed for membrane
penetration (e.g., methotrexate).

40. • Augmented drug extrusion: increased
synthesis of the P-glycoprotein that
extrudes drugs from the cell (e.g.,
anthracyclines, vinca alkaloids,
epipodophyllotoxins, and paclitaxel) is
reponsible for multi-drug resistance (mdr-1
gene amplification).

41. • Diminished bioactivation of a prodrug, e.g.,
cytarabine, which requires intracellular
phosphorylation to become cytotoxic.
• Change in site of action: e.g., increased
synthesis of dihydrofolate reductase may
occur as a compensatory response to
methotrexate.

42. • Damage repair: DNA repair enzymes may
become more efficient in repairing defects
caused by cisplatin.