- Alkylating agents and platinum compounds modify DNA and proteins in cancer cells, interfering with cell division. Bifunctional alkylating agents can cross-link DNA strands, preventing their separation, while monofunctional agents only modify one strand. This DNA damage kills cancer cells but also affects rapidly dividing normal cells.
- Common side effects include nausea/vomiting from 5-HT3 receptor activation, as well as low blood counts affecting immune function and bleeding due to effects on bone marrow. Hair loss, infertility and kidney damage can also occur. Supportive treatments include anti-emetics and hematopoietic growth factors.
- Exposure to sulfur mustard gas in wartime provided early
- Alkylating agents and platinum compounds modify DNA and proteins in cancer cells, interfering with cell division. Bifunctional alkylating agents can cross-link DNA strands, preventing their separation, while monofunctional agents only modify one strand. This DNA damage kills cancer cells but also affects rapidly dividing normal cells.
- Common side effects include nausea/vomiting from 5-HT3 receptor activation, as well as low blood counts affecting immune function and bleeding due to effects on bone marrow. Hair loss, infertility and kidney damage can also occur. Supportive treatments include anti-emetics and hematopoietic growth factors.
- Exposure to sulfur mustard gas in wartime provided early
- Alkylating agents and platinum compounds modify DNA and proteins in cancer cells, interfering with cell division. Bifunctional alkylating agents can cross-link DNA strands, preventing their separation, while monofunctional agents only modify one strand. This DNA damage kills cancer cells but also affects rapidly dividing normal cells.
- Common side effects include nausea/vomiting from 5-HT3 receptor activation, as well as low blood counts affecting immune function and bleeding due to effects on bone marrow. Hair loss, infertility and kidney damage can also occur. Supportive treatments include anti-emetics and hematopoietic growth factors.
- Exposure to sulfur mustard gas in wartime provided early
- Alkylating agents and platinum compounds modify DNA and proteins in cancer cells, interfering with cell division. Bifunctional alkylating agents can cross-link DNA strands, preventing their separation, while monofunctional agents only modify one strand. This DNA damage kills cancer cells but also affects rapidly dividing normal cells.
- Common side effects include nausea/vomiting from 5-HT3 receptor activation, as well as low blood counts affecting immune function and bleeding due to effects on bone marrow. Hair loss, infertility and kidney damage can also occur. Supportive treatments include anti-emetics and hematopoietic growth factors.
- Exposure to sulfur mustard gas in wartime provided early
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
Chemical assault on DNA of cancer cells 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
CH2
alkylating agent
CH2
CH2
CH2
Cl
Cl
+ N
CH2 CH
N guanine (or other intracellular nucleophile)
CH2
N CH2
carbonium ion
CH2 Cl
Chemistry of Bifunctional Alkylating Agent Damage
(continued) N
CH2
N:
CH2 R
CH2
CH
CH2 Cl
adducted guanine
guanine
+ CH2 guanine
CH2
CH2
CH2
CH2 guanine
CH2 CH2 N
R immonium ion
CH2
carbonium ion
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 cells can no longer divide
DNA Cross-links Interfere with Replication
bifunctional alkylating agent cross-link
DNA replication
R N
bifunctional alkylating agent cross-link
Nitrogen Mustards in Clinical Use
CH2
CH2
Cl
CH2
CH2
Cl
CH3 mechlorethamine (nitrogen mustard) HOOC
CH2 CH2 CH2
HOOC CH 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 Characteristics
intravenous
very short (1 minute)
oral oral
1.5 hours 1.5 hours
oral/intravenous intravenous
7 hours 7 hours
rapid action potent vessicant slow rate of conversion to carbonium ion
***must be activated by liver metabolism (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
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 dont live long)
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 Hodgkins 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
(AML) After Treatment for Hodgkins Disease* n = 1329 Hodgkins 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)
Important Take Home Points
Bifunctional vs monofunctional alkylating agents Pharmacologic mechanism of action of alkylators on DNA Side effects of alkylating and platinum agents Chemotherapy induced nausea mechanisms Effects of antineoplastic drugs on gonad function
