Chemical Weapons in the War Against Cancer

What do weapons of mass destruction like mustard gas and sarin have in common with most cancer drugs? Chemistry, of course! This talk will explore the chemistry behind designing life-saving cancer treatments, and how their history is steeped in the dark art of modern poison-making.

Transcript

2. About Me Joseph Szymborski • B.Sc in Biochemistry, McGill University (2015) • M.Sc in Experimental Medicine, McGill University (Ongoing) • Member of Canadian Cancer Society’s Research Information Outreach Team • Very suspicious Google search history @jszym jszym.com Talk Slides
3. Ok, so what’s this talk about? Development and use of Chemical Weapons has led to extremely important Cancer Treatments
4. Ok, so what’s this talk about? Development and use of Chemical Weapons has led to extremely important Cancer Treatments Weaponised Poison
5. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. Definition from the American Heritage® Dictionary of the English Language, Fifth Edition.
6. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. So... basically everything?!
7. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. So... basically everything?! • Dihydrogen Monoxide • Hyponatremia (Coma, Seizures, Respiratory Arrest) • Ethyl Hydroxide • Seizures, Hyperthermia, Renal Failure • Paracetamol • Multiple Organ Failure, Brain Swelling
8. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. So... basically everything?! • Water Dihydrogen Monoxide • Hyponatremia (Coma, Seizures, Respiratory Arrest) • Beer (Drinking Alcohol) Ethyl Hydroxide • Seizures, Hyperthermia, Renal Failure • Tylenol© Paracetamol • Multiple Organ Failure, Brain Swelling
9. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. So... basically everything?! • Water Dihydrogen Monoxide • Hyponatremia (Coma, Seizures, Respiratory Arrest) • Beer (Drinking Alcohol) Ethyl Hydroxide • Seizures, Hyperthermia, Renal Failure • Tylenol® Paracetamol • Multiple Organ Failure, Brain Swelling 6+ Litres1 20+ Pints (5% ABV) = 0.4 BAC2,3 48+ Extra Strength Tablets (500mg) 75+ Regular Tablets (325mg)4
10. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. So... basically everything?! • Water Dihydrogen Monoxide • Hyponatremia (Coma, Seizures, Respiratory Arrest) • Beer (Drinking Alcohol) Ethyl Hydroxide • Seizures, Hyperthermia, Renal Failure • Tylenol® Paracetamol • Multiple Organ Failure, Brain Swelling 6+ Litres1 20+ Pints (5% ABV) = 0.4 BAC2,3 48+ Extra Strength Tablets (500mg) 75+ Regular Tablets (325mg)4 Depends on height, weight, age, genetics, and a million other things... (We get it, you can chug)
11. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal. So... basically everything?! • Cyanide • Arsenic • Sarin 2-3 grains of rice (0.05 – 0.1g) 3-9 grains of rice (0.1g – 0.3g) 2 grains of rice in a Hot Tub (0.03g/m3)
12. What Makes A Poison? Poi·son – n. 1. A substance that causes injury, illness, or death, especially by chemical means. 2. Something destructive or fatal.
13. Modern Chemical Warfare WWI • 1914 – Tear Gas Employed by French (ethyl bromoacetate) • 1915 – Germans Employ First Killing Agent (chlorine gas) • 1915 – French Create Phosgene Gas (much more potent than chlorine) • 1917 – Germany Uses Mustard Gas
14. Mustard Gas (Sulphur Mustard) Step One Gas Exposure
15. Mustard Gas (Sulphur Mustard) Step One Gas Exposure Step Two Cell Death
16. Mustard Gas (Sulphur Mustard) Step One Gas Exposure Step Two Cell Death Step Three Chemical Burns on Exposed Tissue
17. Mustard Gas (Sulphur Mustard) If the next slide doesn’t involve chemistry, I’m going to start violating the Hague Convention
18. Mustard Gas (Sulphur Mustard)
19. DNA! Making Proteins Duplicate DNA 1. RNA Polymerase 2. Ribosome DNA Polymerase
20. DNA! Making Proteins Duplicate DNA DNA RNA/DNA RNA/DNA Polymerase
21. DNA! Making Proteins Duplicate DNA Mustard Gas
22. DNA! Making Proteins Duplicate DNA Mustard Gas
23. DNA! Making Proteins Duplicate DNA Mustard Gas
24. DNA!
25. Mustard Gas (Sulphur Mustard) So help me God, I WILL GAS YOU. GIVE ME THE REAL STUFF!
26. Chemistry Tax
27. DNA, but this time scary.
28. Chemistry Tax
29. Chemistry Tax
30. Chemistry Tax #DONTJUDGECHALLENGE
31. Chemistry Tax
32. Chemistry Tax
33. Chemistry Tax
34. Where is cancer in all this?!
35. “A Curious Observation”
36. Where is cancer in all this?! Mr. J.D. (for our purposes)
37. Where is cancer in all this?! Nitrogen Mustard (HN2, Mustine) Mr. J.D. (for our purposes)
38. Where is cancer in all this?! Nitrogen Mustard (HN2, Mustine) Sulpher Mustard Mr. J.D. (for our purposes)
39. Where is cancer in all this?! Mr. J.D. (for our purposes)
40. O.K., but how does it work?
41. What is Cancer? • A disease where: • Cells divide without control • Can spread to other organs
42. What is Cancer? • A disease where: • Cells divide without control • Can spread to other organs • Caused by • Genetics • Viruses • Environment • Aging • So... basically everything?!
43. What is Cancer? • A disease where: • Cells divide without control • Can spread to other organs • Caused by • Genetics • Viruses • Environment • Aging • So... basically everything?! Normal Breast Duct Early Breast Cancer Lesion
44. Cell Division
45. DNA! Normal Cells DNA Polymerase
46. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
47. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
48. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
49. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
50. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
51. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
52. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
53. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
54. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
55. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
56. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
57. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
58. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
59. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
60. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
61. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
62. DNA! Normal Cells Cancer Cells DNA Polymerase DNA Polymerase
63. So we cured cancer! Right? * Mustardgasol is not real
64. So we cured cancer! Right? = First Ever Chemotherapy
65. So we cured cancer! Right? = Or more specifically an Alkylating antineoplastic agent First Ever Chemotherapy
66. So we cured cancer! Right? = Bendamustine Cisplatin Dacarbazine Temozolomide Leukemia, Lymphoma Most cancers Leukemia, Lymphoma Melanoma, Lymphoma Some Brain Cancers
67. All good things come to an eternal rest Mr. J.D. (for our purposes) ... 6 Months Later
68. Challenges 1. Dosing is hard
69. Challenges 1. Dosing is hard
70. Challenges 1. Dosing is hard
71. Challenges ? ? ? 1. Dosing is hard
72. Challenges 2. Some normal cells are greatly affected Other than tumour cells, chemo attacks: • Hair follicles • Blood Cells • Nail Bed
73. Challenges 2. Some normal cells are greatly affected Other than tumour cells, chemo attacks: • Hair follicles • Blood Cells • Nail Bed • Any other fast-dividing cells Side Effects Include: • Immunosuppression • Gastrointestinal distress • Anemia • Fatigue • Nausea & Vomiting • Hair Loss • Infertility • Cognitive Impairment • Organ Damage • Dry Skin • Damaged Fingernails • Dry Mouth • Sexual Impotence • Peripheral Neuropathy and more!
74. The Solution: Sarin?
75. The Solution: Sarin? 28x More Lethal than Mustard Gas
76. The Solution: Sarin? 28x More Lethal than Mustard Gas Acetylcholine Esterase Neurotransmitter
77. The Solution: Sarin? 28x More Lethal than Mustard Gas Acetylcholine Esterase Neurotransmitter Acetylcholine Neuron Signalling Motor & Sensory Function
78. The Solution: Sarin? 28x More Lethal than Mustard Gas Acetylcholine Esterase Neurotransmitter Sarine Neuron Signalling Motor & Sensory Function
79. The Solution: Sarin? Acetylcholine Esterase Neurotransmitter Sarine Twitching Spasms Coma Suffocation Death
80. The Solution: Targeted Therapy? Bcr-Abl Leukemia (CML)
81. The Solution: Targeted Therapy? Bcr-Abl Imatinib Leukemia (CML)
82. The Vague Take-Away Slide You can only fix something in so far as you can destroy it (... I think)
83. Question Time Talk Slides
84. (A Woefully Incomplete) List of Citations 1. Ballantyne C. Strange but True: Drinking Too Much Water Can Kill [Internet]. Scientific American. [cited 2017 May 10]. Available from: https://www.scientificamerican.com/article/strange-but-true-drinking-too-much-water-can-kill/ 2. Ethanol Level: Reference Range, Interpretation, Collection and Panels. 2017 Jan 7 [cited 2017 May 10]; Available from: http://emedicine.medscape.com/article/2090019-overview 3. Adinoff B, Bone GH, Linnoila M. Acute ethanol poisoning and the ethanol withdrawal syndrome. Med Toxicol Adverse Drug Exp. 1988 Jun;3(3):172–96. 4. Mayhew M. Acetaminophen Toxicity. The Journal for Nurse Practitioners. 2007 Mar 1;3(3):186–8. 5. Haddow A, Kon G, Ross W. Effects upon tumours of Various Haloalkylarylamines. Nature. 1948;162(4125):824–5. 6. Mustard gas – from the Great War to frontline chemotherapy [Internet]. Cancer Research UK - Science blog. [cited 2017 May 15]. Available from: http://scienceblog.cancerresearchuk.org/2014/08/27/mustard-gas-from-the-great-war-to-frontline- chemotherapy/