Transcript Sarcoma chemotherapy

PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Sarcoma Chemotherapy
T R E VOR KWON G
E DM U N D LU K
S I G NED UP : S E PTEMBER 1 2 T H 2 0 1 6
P R ESENTATION DAT E : N OV E M BER 2 3 RD 2 0 1 6
Cancer & Sarcomas
•Cancer is disease in cells characterized by
aberrant cellular proliferation due to
abnormalities in cellular processes regulating
growth.
•Sarcomas are a rare form of malignant cancer
derived from cells of mesenchymal origin: these
include connective tissues such as bones,
muscles, cartilage, blood vessels, and blood.
•Sarcomas vary in their clinical presentation,
disease course, histology grade, growth rate, and
metastatic potential.
Optical Coherence Tomography of a Sarcoma. Retrieved from:
https://en.wikipedia.org/wiki/Sarcoma#/media/File:Nibib_030207_105309_sarcoma.jpg
Cellular Pathways Implicated in Sarcomas
DNA damage, chromosomal translocations, or chromosomal
instability can disable tumor suppressor genes or activate
oncogenes, leading to:
◦ Inhibition of apoptosis
◦ Defective DNA repair pathways
◦ Abnormal growth factor signalling
◦ Abnormal signal transduction pathways
Red:
Induction of
apoptosis
Green:
Cellular
proliferation
(Palmer, 2012)
Anti-Cancer Pharmacotherapy
NON-SPECIFIC CELL DAMAGE
CELL-SPECIFIC: UNIQUE CELLULAR TARGET
Chemotherapy (Cytotoxic Drugs)
Targeted Therapy
◦
◦
◦
◦
Alkylating Agents
Antimetabolites
Topoisomerase Inhibitors
Mitotic Inhibitors
◦ Tyrosine Kinase Inhibitors
Hormonal Therapy
◦ Hormone Antagonists
◦ Aromatase Inhibitors
Immunotherapy
◦ Monoclonal antibody therapy
Chemotherapy
Chemotherapy refers to the usage of non-specific cytotoxic chemical substances to kill
cancerous cells by stimulating the intrinsic (mitochondrial-mediated) pathway of apoptosis.
Cancer cells exhibit higher rates of replication, lower proof-reading, and lower rates of DNA
repair.
Cancer chemotherapy is less selective, more toxic and in some cases, less reliably effective
against cancer, compared to other types of pharmacotherapy which interfere with targets
unique to cancer cells.
There are few drug targets which are unique to only cancer cells.
Cancer cells can develop resistance to anticancer drugs.
The efficacy of cytotoxic drugs depends on the susceptibility of cancer cells with respect to
entering apoptosis.
Cytotoxic Drugs May Target a Specific
Growth Phase
Cell Cycle Specific
◦ Act on cells that are actively dividing.
Phase Specific
◦ Act on specific parts of the cell cycle (G0, G1, S, G2, M).
Cell Cycle Nonspecific
◦ Equal effect with respect to proliferating and resting states.
Cytotoxic Drugs Classified by Mechanism
of Action
Alkylating Agents
Antimetabolites
Topoisomerase Inhibitors
Mitotic Inhibitors
Alkylating Agents
Covalent modification of DNA interferes with the action of enzymes
involved in DNA replication, either through crosslinking or by
interfering with access to DNA. These mechanisms stimulate
apoptosis.
Alkylating agents are not limited to actively dividing cells: they are
cell cycle nonspecific.
Ifosfamide and Cisplatin Induce GuanineGuanine Crosslinking in DNA
Ifosfamide
Activated by CYP450
Cisplatin
Isophosphoramide Mustard is an Active
Metabolite of Ifosfamide
Nu = N(7) of Guanine
(Springer et al., 1998)
Nucleic Acid Drug Interactions: Cisplatin and Trans-platin (2016). Retrieved from http://www.atdbio.com/content/16/Nucleic-acid-drug-interactions
Methotrexate is DHFR Antimetabolite
Antimetabolites masquerade as the normal substrate, competing for the active side of the
enzyme or receptor.
Dihydrofolate reductase (DHFR) catalyzes the formation of tetrahydrofolate (THF) from
dihydrofolate (DHF).
Methotrexate competitively binds DHFR.
THF is required for purine, thymidylate, methionine, and glycine synthesis.
Methotrexate is more active against S-Phase cells.
Folate
Methotrexate
Folate and Methotrexate. Retrieved from:
https://upload.wikimedia.org/wikipedia/commons/2/21/Methotrexate_vs_f
olate.svg
Gemcitabine is a Deoxycytidine
Antimetabolite
Gemcitabine (dFdC) is activated by deoxycytidine kinase into its diphosphate (dFdCDP) and
triphosphate (dFdCTP) form.
Incorporation of nucleotide analogs into DNA stops DNA replication by terminating elongation.
Gemcitabine also inactivates Ribonucleotide Reductase, through covalent binding.
Ribonucleotide Reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides.
A lowered dNTP pool promotes a higher degree of gemcitabine phosphorylation, and reduces
dCTP levels needed for DNA synthesis.
(Cavalcante et al., 2014)
Doxorubicin Inhibits DNA Topoisomerase II
Topoisomerase II relaxes DNA supercoiling during transcription.
Doxorubicin intercalates with DNA and stabilizes the DNAtopoisomerase II complex.
The DNA double helix cannot be resealed, stopping cell replication and
inducing apoptosis.
Phase-specific G2.
Although not the major mode of action, DNA-adducts can also induce
apoptosis independent of topoisomerase II.
(Yang et al., 2014)
Docetaxel Inhibits Mitosis by Binding
Tubulin
Microtubules are involved in cell proliferation, trafficking, signalling,
and migration.
Docetaxel stabilizes the microtubule, preventing microtubule
depolymerisation.
Free tubulin is sequestered.
Overall inhibition of mitotic cell division due to lack of microtubule
formation, between metaphase and anaphase.
(Montero et al., 2005)
Some Negative Side Effects of
Chemotherapy
Immunosuppression
Hair Loss
Gastrointestinal Distress
Infertility
Anemia
Teratogenicity
Fatigue
Peripheral Neuropathy
Nausea
Cognitive Impairment
Organ Damage
The Story of Terry Fox
Born in 1958 in Winnipeg, Manitoba.
Suffered from a malignant osteogenic sarcoma in his
right leg which was discovered in 1977.
Had leg amputated 15 cm above the knee.
Marathon of Hope: Ran across Canada to raise
money for cancer research–at least $1 for every
Canadian.
Died in June 1981.
The Terry Fox Foundation is remains a strong
powerhouse for funding cancer research initiatives.
Donate and participate in the Terry Fox
Run in September!
Summary
Cancer is a disease in cells characterized by aberrant cellular proliferation due to abnormalities in cellular processes regulating growth; it
can be either benign or malignant. Some pathways implicated in the development of cancer include defective tumor suppressor genes,
abnormal signal transduction pathways, and abnormal growth factor signaling.
Sarcomas are a rare form of malignant cancer which grows in mesenchymally derived connective tissues such as bones, muscles,
cartilage, blood vessels, and blood.
Chemotherapy refers to the usage of non-specific cytotoxic chemical substances to kill cancerous cells by stimulating apoptosis. Higher
rates of replication and impaired DNA repair pathways contribute to a greater cytotoxic effect on cancer cells. The inability for cytotoxic
drugs to discriminate between healthy and cancerous cells leads to the toxic side-effects associated with chemotherapy.
Cytotoxic drugs can act on a specific phase of the cell cycle:
◦ Cell cycle specific - Act on cells that are actively dividing.
◦ Phase specific - Act on specific parts of the cell cycle (G1, S, G2, M).
◦ Cell cycle nonspecific - Equal effect with respect to proliferating and resting states.
Cytotoxic drugs have a variety of different mechanisms, all of which damage cells to activate the intrinsic pathway of apoptosis:
◦ Alkylating agents – Damage DNA through covalent modification: for example, cross-linking of guanine-guanine residues in DNA.
◦ Antimetabolites – Substrate analogs which compete with the normal substrate to interfere with normal enzymatic activity. Examples include nucleotide
analogs, which can result in chain-termination upon incorporation, and antifolate compounds, which act as competitive inhibitors to DHFR.
◦ Topoisomerase inhibitors – Interfere with topoisomerases, resulting in the inability for cells to continue replication.
◦ Mitotic inhibitors - Prevents cells from replicating in the mitotic phase of growth by interfering with microtubule formation or depolymerization.
References
Cavalcante, L. S., Monteiro, G. (2014). Gemicitabine: Metabolism and Molecular Mechanisms of Action. Sensitivity, and Chemoresistance in Pancreatic Cancer.
European Journal of Pharmacology, (741): 8-16.
Galmarini, C. M., Mackey, J. R., Dumontet, C. (2001). Nucleoside Analogues: Mechanisms of Drug Resistance and Reversal Strategies. Leukemia, (15): 875-890.
Genestier, L., Paillot, R., Quemeneur, L., Izeradjene, K., Revillard, J. P. (2000). Mechanisms of Action of Methotrexate. Immunopharmacology, (47): 247-257.
Hannun, Y. A. (1997). Apoptosis and the Dilemma of Cancer Chemotherapy. Blood, 89 (6): 1845-1853.
Mastropaolo, D., Camerman, A., Luo, Y., Brayer, G. D., Camerman, N. (1995). Crystal and Molecular Structure of Paclitaxel (Taxol). Proc. Natl. Acad. Sci., (92): 69206924.
Montero, A., Fossella, F., Hortobagyi, G., Valero, V. (2005). Docetaxel for Treatment of Solid Tumors: A Systematic Review of Clinic Data. Lancet Oncol., (6): 229-239.
Palmer, M. (2012). Cancer Chemotherapy. 227-247.
Payne, S., Miles, D. (2008). Mechanisms of Anticancer Drugs. 34-46.
Shor, A. C., Agresta, S. V., D’Amato, G., Sondak, V. K. (2008). Therapeutic Potential of Directed Tyrosine Kinase Inhibitor Therapy in Sarcomas. Cancer Control, 15 (1):
47-54.
Springer, J. B., Colvin, M. E., Colvin, O. M., Ludeman, S. M. (1998). Isophosphoramide Mustard and Its Mechanism of Bisalkylation. J. Org. Chem., (63): 7218-7222.
Yang, F., Teves, S. S., Kemp, C. J., Henikoff, S. (2014). Doxorubicin, DNA Torsion, and Chromatin Dynamics. Biochem. Biophys. Acta., 1845 (1): 84-89.
Online References
Mission Statement and History. (n.d.). Retrieved November 10, 2016, from http://www.terryfox.org/TerryFox/Mission_Statement.html
Types of chemotherapy - Canadian Cancer Society. (n.d.). Retrieved November 09, 2016, from http://www.cancer.ca/en/cancer-information/diagnosisand-treatment/chemotherapy-and-other-drug-therapies/chemotherapy/types-of-chemotherapy/?region=on
Chemotherapy Drugs: How They Work - American Cancer Society. (n.d.). Retrieved November 15, 2016, from
http://www.cancer.org/acs/groups/cid/documents/webcontent/002995-pdf.pdf
How Chemotherapy Drugs Work. (n.d.). Retrieved November 10, 2016, from
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/how-chemotherapy-drugs-work
Drugs - Anti-cancer. (n.d.). Retrieved November 10, 2016, from http://chemistry.elmhurst.edu/vchembook/655cancer2.html
How chemotherapy works - Canadian Cancer Society. (n.d.). Retrieved November 08, 2016, from http://www.cancer.ca/en/cancer-information/diagnosisand-treatment/chemotherapy-and-other-drug-therapies/chemotherapy/how-chemotherapy-works/?region=on
Types of Chemotherapy Drugs. (n.d.). Retrieved November 12, 2016, from http://chemoth.com/types
What is Sarcoma? - Sarcoma Alliance. Retrieved November 15, 2016, from http://sarcomaalliance.org/what-you-need-to-know/what-is-sarcoma/
Chew, A., Dr, & DeZorzi, P. (n.d.). Retrieved November 13, 2016, from http://www.pedsoncologyeducation.com/chemotherapyclassifaction.asp
Types of treatment for soft tissue sarcoma. (n.d.). Retrieved November 7, 2016, from http://www.cancerresearchuk.org/aboutcancer/type/sarcoma/treatment/which-treatment-for-soft-tissue-sarcoma
DNA Topoisomerase. (n.d.). Retrieved November 10, 2016, from https://www.ebi.ac.uk/interpro/potm/2006_1/Page2.htm