Chemotherapy Rotations: Alkylating Agents and Platinum Compounds Nicole Shilkofski, M.D.
Learning Objectives • Explain mechanisms of alkylating agents, discriminating key differences between bifunctional and monofunctional agents in creating inter-strand cross-links in cancer cell DNA. • Understand the likely mechanisms of action of platinum compounds and the association of antineoplastic platinum compounds and kidney damage . • Gain familiarity with common side effects associated with anti-neoplastic drug administration, including neutropenia, anemia, thrombocytopenia, hair loss, and gonadal dysfunction
Learning Objectives • Explain mechanisms of alkylating agents, discriminating key differences between bifunctional and monofunctional agents in creating inter-strand cross-links in cancer cell DNA. • Understand the likely mechanisms of action of platinum compounds and the association of antineoplastic platinum compounds and kidney damage . • Gain familiarity with common side effects associated with anti-neoplastic drug administration, including neutropenia, anemia, thrombocytopenia, hair loss, and gonadal dysfunction
Alkylating Antineoplastic Agents • “Chem “Chemic ical al assau assault lt”” on DNA DNA of cance cancerr cell cellss • Modify functional groups on genomic DNA and protein of cells (attaches alkyl group to DNA- usually guanine base of DNA, most commonly number 7 nitrogen atom of purine ring) • Explains both ability to kill cancer cells via DNA damage but also cytotoxic effects on cells that divide frequently (GIT, bone marrow, testicles, ovaries)
History of Chemical Warfare: Exposure to Alkylating Agents in Wartime: World War II- December 1943
Sulfur mustard gas is generated when sulfur chloride is added to ethylene An estimated 9,000,000 shells filled with sulfur mustard were fired in World War I with some 1,205,655 nonfatal casualties and 91,198 deathsskin burns, alkylation of nerve endings in diaphragm= major cause of death
Side effects post gas experienced similar to antineoplastic agents (hair loss, alterations in blood counts etc.)
WWII: Bombing in ItalyUS Liberty ship, which had been carrying a secret cargo of 2,000 M47A1 World War I type mustard gas bombs, each of which held 60-70 lbs of sulfur mustard
Within a day, symptoms of mustard poisoning began appearing in rescued casualties, in medical personnel, and in local residents (among military personnel, 628 became blind and developed chemical burns; 83 ultimately died); medical personnel described a “garlic-like” odor A young medical officer described the striking reduction in white blood cell counts, particularly in lymphocyte counts, in addition to the expected chemical burns
Reactive Nucleophiles in DNA
Drugs are electophiles- modify nucleophiles in DNA: N7 position of Guanine is most commonly modified
Bifunctional vs monofunctional Alkylating Agents • Bifunctional (dialkylating)- can react with 2 different residues resulting in cross linkage (antineoplastic drugs) • Monofunctional (monoalkylating)- can react with only one N7 of guanine so do not prevent separation of DNA strands of helix but prevent DNA processing enzymes from accessing DNA (mutagens and carcinogens)
Chemistry of Bifunctional Alkylating Agent Damage Cl CH2 R
immonium ion CH2
CH2
N:
R CH2
N
+
CH2
alkylating agent
CH2
CH2
CH2
Cl
Cl
+
N CH N
guanine (or other intracellular nucleophile)
CH2
R
CH2
N CH2
carbonium ion
CH2 Cl
Chemistry of Bifunctional Alkylating Agent Damage (continued) N
+
CH2
N:
CH2 R
CH2
CH
CH2 Cl
N
adducted guanine
guanine
CH2 guanine
CH2
CH2
N
+
CH2
+
guanine
CH2
CH2 CH2 N
R immonium ion
CH2
carbonium ion
R
Interstrand DNA Cross-link Caused by Bifunctional Alkylating Agent
Stop tumor growth by crosslinking guanine nucleobases in DNA double helix strands so strands cannot uncoil and separate and
DNA Cross-links Interfere with Replication
bifunctional alkylating agent cross-link
N R
DNA replication
R N
bifunctional alkylating agent cross-link
Nitrogen Mustards in Clinical Use
R
N
CH2
CH2
Cl
CH2
CH2
Cl
CH3 mechlorethamine (nitrogen mustard) HOOC
HOOC
CH
CH2 CH2 CH2
CH2
chlorambucil
NH2 melphalan (L-phenylalanine mustard; (L-PAM)
N O
NH O
P O
cyclophosphamide
P O
CH2 NH
CH2 CH2
ifosfamide
Cl CH2
Cl
Pharmacology of the Nitrogen Mustards
Drug
Principal Route of Administration
mechlorethamine
chlorambucil melphalan
cyclophosphamide ifosfamide
Plasma t1/2
intravenous
very short (1 minute)
oral oral
1.5 hours 1.5 hours
oral/intravenous intravenous
7 hours 7 hours
Characteristics
rapid action potent vessicant slow rate of conversion to carbonium ion ***mu st be a c t i v a t ed b y l i v er m e t ab o l i s m
(prodrugs)
Toxicities of the Nitrogen Mustards Drug
Acute
Delayed (Dose-Limiting)
mechlorethamine severe nausea/vomiting, bone marrow suppression, phlebitis/skin irritation amenorrhea chlorambucil
nausea/vomiting
bone marrow suppression
melphalan
mild nausea
bone marrow suppression
cyclophosphamide
nausea/vomiting
bone marrow suppression, hemorrhagic cystitis, alopecia, amenorrhea, sterility, water retention
ifosfamide
nausea/vomiting
bone marrow suppression, hemorrhagic cystitis, alopecia, neurotoxicity, water retention
Platinum based chemotherapy drugs • Often called “Alkylating like” drugs • Do not have an alkyl group but still damage DNA by interfering with DNA repair • Also bind at N7 of guanine
Platinum Compounds: Cisplatin Cross-Links to DNA and Protein
Platinum Compounds in Clinical Use O NH2
NH2
Pt
Pt Cl
NH2
O O
Cl
O carboplatin
cisplatin O
NH2
O Pt O O
NH2 oxaliplatin
NH2
Pharmacology of the Platinum Compounds Drug
cisplatin
Principal Route of Administration intravenous intraperitoneal
Plasma t1/2
20-40 minutes
Characteristics
Rapid reaction; 30-50% of drug excreted in urine within 24 hours (therefore has side effect of kidney damage)
carboplatin
oxaliplatin
intravenous
intravenous
2-3 hours
Slow reaction
2-3 hours
Slow reaction
Toxicities of the Platinum Compounds Drug
cisplatin
carboplatin
oxaliplatin
Acute
severe nausea/vomiting, anaphylactic reactions
moderate nausea/ vomiting
nausea/vomiting
Delayed (Dose-Limiting)
***nephrotoxicity, ototoxicity, peripheral neuropathy, bone marrow suppression
bone marrow suppression
bone marrow suppression, neurotoxicity, diarrhea
Chemotherapy-Induced Nausea and Vomiting cerebral cortex
metabolic disorders: Uremia, ketoacidosis, hypoxia
chemoreceptor trigger zone (area postrema)
anticipitory emesis: elicited by chemotherapy (before administration)
vomiting center
motion sickness inner ear disorders
(neural networks in the nucleus tractus solitarius)
drugs: opiates, anesthetic agents, cardiac glycosides, chemotherapy (immediate)
peripheral receptors (vagal and splanchnic nerves)
vestibular center intestinal injury toxins chemotherapy (late) radiation therapy
Treatment and Prophylaxis of ChemotherapyInduced Nausea and Vomiting anti-emetic
mechanism of action
selective serotonin type 3 (5-HT3) receptor antagonists ondansetron, granisetron dolasetron
5-HT3 receptor blockade
benzamides metoclopramide corticosteroids dexamethasone, methylprednisolone phenothiazines prochlorperazine promethazine, thiethylperazine
dopamine and 5-HT3 receptor blockade
benzodiazepines lorazepam butyrophenones haloperidol, droperidol cannabinoids dronabinol, nabilone
anxiolytic, amnesic
unknown dopamine receptor blockade
dopamine receptor blockade general psychotropic
Other Toxicities: Effects on Rapidly Replicating Cell Populations
hematopoietic stem cells are resistant to cyclophosphamide
Timing of Chemotherapy-Induced Neutropenia Dose affects severity but not timing of decrease in ANC
Treatment of Chemotherapy-Induced Bone Marrow Dysfunction Transfusion of blood components red blood cells platelets granulocytes (rare- cells don’t live long)
Hematopoietic cytokines erythropoietin G-CSF (filgrastim) GM-CSF (sargramostim)
Effect of G-CSF Treatment on ChemotherapyInduced Neutropenia daily G-CSF chemotherapy
Chemotherapy Effects on Gonadal Function Age/Gender pubertal (non-proliferating) gonads remarkably resistant to cytotoxic effects of anti-neoplastic drugs breast cancer treatment: AC (doxorubicin/cyclophosphamide) amenorrhea 96% women age 40-49 versus 0% women age <30) male gonads more sensitive than female gonads
Chemotherapy agent(s) and dose, other cancer therapy alkylating agents/platinum compounds particularly bad Hodgkin’s disease treatment: MOPP (alkylating agents) with 97% azoospermia (13% recovery) 70% versus 10% recovery of spermatogenesis in boys after treatment with cyclophosphamide at lower vs higher doses
exogenous chemotherapy carcinogens other toxins/irritants
endogenous metabolism inflammation cell signaling many enzymes
cytochrome P450's
oxidants electrophiles
inactivated detoxification (GSTP1, GSTs, GPx, etc.)
cell death repair
proliferation
transformation mutation
genome damage
Chemotherapy-Associated Acute Myeloid Leukemia (AML) After Treatment for Hodgkin’s Disease* n = 1329 Hodgkin’s disease survivors treatment actuarial risk of AML ________________________________ RT alone
0%
chemotherapy alone
1.4% +/- 2.3%
RT + MOPP (alkylators)
10.2% +/- 5.2%
RT + other alkylators
4.8% +/- 1.6%
*Valagussa et al. J Clin Oncol 4: 830 (1986)
