Introduction to chemotherapy

1. T I T L E : C H E M O T H E R A P Y I N TA R G E T I N G C E L L U L A R
T R A N S F O R M AT I O N P R O C E S S F O R C A N C E R
P R E V E N T I O N A N D T R E AT M E N T.

2. • Cell division occurs in an uncontrolled behavior which leads to constant growing and division of the
cell.
• Mutation in gene or damage DNA structure
• Features of cancerous cells :
- Cancer cells does not undergoes normal cell cycles
- Cancer does not stop growing and dividing
- Cancer cells ignore apoptosis signals from other cells
(eg. HER2)
- Cancer cells don’t stick together. Having the ability to detach from neighbouring cells. (eg. APC)
- Cancer cell does not specialise.
- Cancer cell does not undergo cell repair nor undergo apoptosis.
• Types of treatment (NIH, n.d.) :
- Surgery
- Radiation Therapy
- Immunotherapy
- Chemotherapy
- Hormone therapy
W H A T ’ S C A N C E R ?

3. • Chemotherapy refers to the use of medication that circulates in the body to kill cancer
cells.
• Controlling the division and spread of cancerous cell.
• Goals of chemotherapy :
- Cure
- Control
- Palliation
• Sources of drugs :
- Plants
- Manufactured
• Type of chemotherapy drugs :
- Antimetabolites ( Pentostatin )
- Mitotic Inhibitors ( Taxanes )
I N T R O D U C T I O N O N C H E M O T H E R A P Y
Figure 1 : Impact of cytotox chemotherapy
on 5-year survival in Australian adults.
( Morgan, Ward & Barton 2004)

4. • Alkylating Agent (Sulfur Mustard) :
- Induce DNA damage resulting poly(ADP-ribose) polymerase (PARP) activation.
( Kehe et al. 2009)
- Overactivation deplets cellular NAD(+) and ATP levels.
- Induced cellular necrosis. (Ricci & Zong 2016)
• Anti-Metabolities (Methotrexate)
- Interfere with normal metabolic process within cells. (Kaye 1998)
- Inhibition of de novo purine synthesis.
- Disrupting cell repair and cell replication. (Allegra et al. 1987)
• Anti-Tumour Antibiotics (Anthracyclines)
- Interfere with enzymes involved in DNA replication
- Examples : doxorubicin , daunorubicin
- Inhibition transcriptional activity and tumor induced mobilization of circulating
angiogenic cells. (Lee et al. 2009)
H O W C H E M O T H E R A P Y W O R K S I N P R E V E N T I N G C E L L U L A R
T R A N S F O R M A T I O N ?

5. • Topoisomerase Inhibitor
- Interfere with Topisomerase II, generating enzyme mediated DNA damage.
- Classified into :
a. First Class : increases in the levels of Topoisomerase II DNA covalent
complexes.
b. Second Class : inhibits Topoisomerase II catalytic activity. (Nitiss 2009)
• Mitotic Inhibitor
- Disruption of mitotic progression. (Gascoigne & Taylor 2009)
-
H O W C H E M O T H E R A P Y W O R K S I N P R E V E N T I N G C E L L U L A R
T R A N S F O R M A T I O N ?
Figure 2: Cell fate in response to anti-mitotic
drug treatment. (Gascoigne & Taylor 2009)

6. • Uses genes as a form of treatment for cancer
- Insertion of normal gene into the cancer cells
- Replace the mutated gene or perform genetic modification to induce silent
mutation.
- Genetic approach to target cancer cell apoptosis.
• Examples :
- Targets mutated p53 protein by introducing a normal
p53 gene along with tumor suppressor gene.
- Promote cell apoptosis.
• Examples :
- Silencing endogenous cancer intracellular
immune suppressor proteins.
- Inhibits expression of genes activation
and over expression in cancer cells.
F U T U R E P R O S P E C T ( C H E M O T H E R A P Y )
Image 3 : Mechanism of RNAi.
(Alnylam Pharmaceuticals n.d.)

7. • Future developments in chemotherapy are slow to progress but
targets to :
- Focus on development of administration techniques.
- Increasing therapeutical agents efficacy and safety.
• Example: Prodrugs.
- Medication released at controlled method.
• Studies on new drug releasing strategy through tumour specific
characteristic such as :
- pH
- expression of tumour associated enzyme.(Martins & de Oliveria
2008)
C U R R E N T D E V E L O P M E N T A N D L I M I TA T I O N O F C H E M O T H E R A P Y

8. • Modification of current stages of cancer
- Residual component of medication may be left behind even after surgery.
- Causes of over-treatment. (Ikeda et al 2002)
• Significant lower cure rates in chemotherapy :
- logistically challenges of applying and properly supervising intake of chemotherapy.
(Nuermberger et al 2010)
• Possibilites of drug-resistant tumour.
- Tumour escaping from toxic effect of common chemotherapy drugs.
- Causes development of progressive disease.
- Two classes of transporter protein responsible of multidrug resistance in chemotherapy :
a. ATP-binding cassette transporter superfamily.
b. Solute carrier transporter superfamily. (Liu 2009)
• High cost of chemotherapy drug :
- Laboratory findings
- High cost of treatment contradicting with efficacy of drug. (Siddiqui & Rajkumar 2012)
L I M I TA T I O N O F C H E M O T H E R A P Y

9. R E F E R E N C E S
• Allegra, CJ, Hoang, K, Yeh, GC, Drake, JC & Baram, J 1987, ‘Evidence for Direct Inhibition of de Novo Purine Synthesis in Human
MCF-7 Breast Cells as a Principal Mode of Metabolic Inhibition’, The Journal Of Biological Chemistry, vol.262, no. 28, pp. 13520 -
13526.
• Alnylam Pharmaceuticals, n.d., RNA interference, viewed 21 April 2016,
<http://www.alnylam.com/rnai_primer/rna-interference-pg5.htm>
• Gascoigne, KE & Taylor, SS 2009, ‘How do anti-mitotic drugs kill cancer cells?’, Journal of Cell Science, vol. 122, pp. 2579 - 2585.
• Hanahan, D & Weinberg, R 2000, 'The Hallmarks of Cancer', Cell, vol. 100, no. 1, pp. 57-70.
• Ikeda T., Jinno H., Matsu A., Masamura S., Kitajima M. 2002, ‘The role of neoadjuvant chemotherapy for breast cancer treatment’,
Breast Cancer, Vol. 9, no. 1, pp. 8-14.
• Kaye, SB, 1998, ‘New antimetabolites incancer chemotherapy and their clinical impact’, British Journal of Cancer, vol 78, no. 3, pp.1 - 7.
• Kehe, K, Balszuwelt, F, Steinritz, D & Thiermann, H ‘Molecular toxicology of sulfur mustard-induced cutaneous inflammation and
blistering.’, Toxicology, vol. 263 no. 1, pp. 12 - 19.
• Lee, KA, Qian, DZ, Rey, S, Wei, H, Lie, JO & Semenza, GL 2009, ‘Anthracycline Chemotherapy Inhibits HIF-1 Transcriptional Activity and
Tumor-Induced Mobilization of Circulating Angiogenic Cells’, National Academy of Sciences, Vol. 106, No. 7, pp. 2353-2358.
• Liu FS 2009, ‘Mechanisms of chemotherapeutic drug resistance in cancer therapy –a quick review’, Taiwan Journal of Obstetrics and
Gynecology, Vol. 48, no. 3, pp. 239-44.
• Morgan, G, Ward, R & Barton, M 2004, ‘The Contribution of Cytotoxic Chemotherapy to 5-year Survival in Adult Malignancies’, Clinical
Oncology, vol. 16, pp. 549 - 560.

10. R E F E R E N C E S
• NIH, n.d., Types of treatment, viewed 21 April 2016
<http://www.cancer.gov/about-cancer/treatment/types>
• Nitiss, JL 2009, ‘Targeting DNA topoisomerase II in cancer chemotherapy’, Nat Rev Cancer, vol. 9,
no. 5, pp. 335 - 350.
• Nuermberger EL, Spigelman MK, Yew WW. 2010, ‘Current development and future prospects in
chemotherapy of tuberculosis.’, Respirology, vol. 15, no. 5, pp. 764-78.
• Ricci, MS & Zong, WX 2006, ‘Chemotherapeutic Approaches for Targeting Cell Death Pathways’,
Oncologist, vol 11, no.4 pp. 342 - 357.
• Siddiqui, M., & Rajkumar, S. V. 2012, ‘The High Cost of Cancer Drugs and What We Can Do About
It’. Mayo Clinic Proceedings, Vol. 87, no. 10, pp 935–943.