Cancer Chemotherapy Cancer Chemotherapy

Cytotoxic Cytotoxic Drugs Drugs

Musbah Musbah Omar Omar Tanira Tanira
ormal cells. ormal cells.
differentiate, grow, mature, divide differentiate, grow, mature, divide
regulated, balanced; cell birthcell death regulated, balanced; cell birthcell death
regulation: regulation: intracell intracell signaling signaling
eoplasia eoplasia .. ~abnormal growth/invasion of cells .. ~abnormal growth/invasion of cells
~new growth ~new growth
irreversible irreversible
cells replicate cells replicate
grow without control grow without control
eoplasms eoplasms/Tumors /Tumors
groups of groups of neoplastic neoplastic cells cells
Benign Benign -- ~noncancerous ~noncancerous
local; cells cohesive, well local; cells cohesive, well- -defined borders defined borders
push adjacent tissue away push adjacent tissue away
doesn`t spread beyond original site doesn`t spread beyond original site
often has capsule of fibrous connective tissue often has capsule of fibrous connective tissue
Malignant Malignant -- grow more rapidly; often called ~cancer grow more rapidly; often called ~cancer
not cohesive; seldom have capsule not cohesive; seldom have capsule
irregular shape; disrupted architecture irregular shape; disrupted architecture
invade surrounding cells invade surrounding cells
metastasis metastasis
nticancer Chemotherapy: Principles nticancer Chemotherapy: Principles
totoxic totoxic Drugs Drugs Act at ell cle Act at ell cle
Anllcuncer Chemolherupy: Prlnclples Anllcuncer Chemolherupy: Prlnclples
totoxic totoxic Drugs are " Drugs are "Antiproliferative Antiproliferative""
ffect cell division ffect cell division
active on rapidly dividing cells active on rapidly dividing cells
Most effective during S phase of cell cycle Most effective during S phase of cell cycle
many cause D damage many cause D damage
Damage D Damage D initiating apoptosis to all susceptible cells: initiating apoptosis to all susceptible cells:
cancerous cancerous or or normal normal
Anllcuncer Chemolherupy: Prlnclples Anllcuncer Chemolherupy: Prlnclples
totoxic totoxic drugs act in accordance to the log drugs act in accordance to the log kill kill hpothesis hpothesis
ccording to the log ccording to the log- -kill hypothesis, kill hypothesis, cytotoxic cytotoxic drugs drugs kill a constant kill a constant
fraction fraction of cells of cells f first order kinetics irst order kinetics), ), rather than a specific number rather than a specific number
of cells, after each dose of cells, after each dose
solid solid cancer tumors cancer tumors - - generally have a generally have a low growth fraction low growth fraction
thus thus respond poorly to chemotherapy respond poorly to chemotherapy and and in most cases need in most cases need
to be removed by to be removed by surgery surgery
disseminated disseminated cancers cancers- - generally have a generally have a high growth fraction high growth fraction
and and generally generally respond well to chemotherapy respond well to chemotherapy
Anllcuncer Chemolherupy: Prlnclples Anllcuncer Chemolherupy: Prlnclples
ctotoxic ctotoxic drugs are used in combination drugs are used in combination
Combinations of agents with differing toxicities Combinations of agents with differing toxicities and mechanisms and mechanisms of of
action are often employed to overcome the limited cell kill of action are often employed to overcome the limited cell kill of
individual individual cytotoxic cytotoxic agents agents. Each drug selected should be . Each drug selected should be
effective alone effective alone
dvantages dvantages of combination therapy: of combination therapy:
suppression suppression of drug resistance of drug resistance - - less chance of a cell less chance of a cell
developing resistance to 2 drugs than to 1 developing resistance to 2 drugs than to 1 drug drug
increased increased cancer cell kill cancer cell kill - - administration of drugs with administration of drugs with
different mechanisms of different mechanisms of action action
reduced reduced injury to normal cells injury to normal cells - - by using a combination of by using a combination of
drugs that do not have overlapping toxicities, we can achieve drugs that do not have overlapping toxicities, we can achieve
a greater anticancer effect than we could by using any one a greater anticancer effect than we could by using any one
agent agent alone alone
Treatment
Time (linear scale)
ormal cells
Tumour cells
The Effect of The Effect of Cytotoxic Cytotoxic Therapy: Single Course Therapy: Single Course
Treatment 1
Time (linear scale)
ormal cells
Tumour cells
Treatment 2
Treatment 3
The Effect of The Effect of Cytotoxic Cytotoxic Therapy: Multiple Therapy: Multiple Cources Cources

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.

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f

c
e
l
l
s
Time (linear scale)
ormal cells
Tumour cells
Multiple Courses of Multiple Courses of Cytotoxic Cytotoxic Therapy Therapy
with Too Long an Interval with Too Long an Interval
Log kill Log kill hypothesis! hypothesis!
LOG kill hypothesis LOG kill hypothesis
The example shows the effects The example shows the effects
of tumor burden, scheduling, of tumor burden, scheduling,
initiation/duration of initiation/duration of
treatment on patient survival treatment on patient survival..
The tumor burden in an The tumor burden in an
untreated patient would untreated patient would
progress along the path progress along the path
described by the described by the RED LIE RED LIE
The The tumor is detected (using tumor is detected (using
conventional techniques) conventional techniques)
when the tumor burden when the tumor burden
reaches 10 reaches 10
99
cells cells
The patient is symptomatic at The patient is symptomatic at
10 10
10 10
- -10 10
11 11
cells cells
Dies at 10 Dies at 10
12 12
cells. cells.
nticancer Chemotherapy: Principles nticancer Chemotherapy: Principles
#esistance #esistance to to totoxic totoxic Drugs: Modes Drugs: Modes
Mechanism Mechanism Drugs or Drug Groups Drugs or Drug Groups
Change in sensitivity (or level) or Change in sensitivity (or level) or
binding affinity of target enzymes or binding affinity of target enzymes or
receptors receptors
Etoposide Etoposide, , methotrexate methotrexate, , vinca vinca alkaloids alkaloids, ,
estrogen & androgen receptors estrogen & androgen receptors
Decreased drug accumulation via Decreased drug accumulation via
expression of glycoprotein transporters, expression of glycoprotein transporters,
or permeability or permeability
Methotrexate Methotrexate, , alkylating alkylating agents, agents,
dactinomycin dactinomycin
Formation of drug Formation of drug- -inactivating enzymes inactivating enzymes Purine Purine & & pyrimidine pyrimidine antimetabolites antimetabolites
Production of reactive chemicals that Production of reactive chemicals that
~trap the anticancer drug ~trap the anticancer drug
lkylators lkylators, , bleomycin bleomycin, , cisplatin cisplatin. .
doxorubicin doxorubicin
Increased nucleic acid repair mechanisms Increased nucleic acid repair mechanisms lkylating lkylating agents, agents, cisplatin cisplatin
Reduced activation of pro Reduced activation of pro- -drugs drugs Purine Purine & & pyrimidine pyrimidine antimetabolites antimetabolites
Resistance to Resistance to Cytotoxic Cytotoxic Drugs Drugs
MDR1 Example MDR1 Example
- - increased expression of increased expression of
MDR MDR- -1 gene for a cell 1 gene for a cell
surface P surface P- -glycoprotein glycoprotein
- - MDR MDR- -1 gene is involved 1 gene is involved
with drug efflux with drug efflux
- - drugs that reverse MDR : drugs that reverse MDR :
verapamil verapamil, , quinidine quinidine,,
cyclosporine cyclosporine
- - MDR increases resistance MDR increases resistance
to natural drug products to natural drug products
including the including the anthracyclines anthracyclines, ,
vinca vinca alkaloids, and alkaloids, and
epipodophyllotoxins epipodophyllotoxins
Proliferating cells Proliferating cells are are
especially sensitive to especially sensitive to
chemotherapy because chemotherapy because
cytotoxic cytotoxic drugs drugs usually act usually act
by by disrupting D synthesis disrupting D synthesis
or mitosis or mitosis, cellular activities , cellular activities
that only proliferating cells that only proliferating cells
carry carry out out
Unfortunately, toxicity to the Unfortunately, toxicity to the
anticancer agents is to any anticancer agents is to any
rapidly dividing cells. (e.g. rapidly dividing cells. (e.g.
bone marrow, hair follicles, bone marrow, hair follicles,
sperm forming cells sperm forming cells) )
BMS, BMS, impaired wound impaired wound
healing, hair follicle damage, healing, hair follicle damage,
Gi Gi epith epith damage , growth in damage , growth in
children, children, gametes, gametes,
teratogenicity teratogenicity, ,
carcinogenicity carcinogenicity
Toxicity to High Growth Fraction Toxicity to High Growth Fraction
vs. Low Growth Fraction. vs. Low Growth Fraction.
Cytotoxic Cytotoxic Drugs: DRs Drugs: DRs
Tissue Undesirable Effects
Bone marrow Leukopenia and resulting inIections
Immunosuppression
Thrombocytopenia
Anemia
GI tract Oral or intestinal ulceration
Diarrhea
Hair Iollicles Alopecia
Gonads Menstrual irregularities, including premature
menarche; impaired spermatogenesis
Wounds Impaired healing
Fetus Teratogenesis (especially during Iirst trimester)

Prevention/Management Prevention/Management of of
Drug Drug- -Induced Toxicities Induced Toxicities
The toxicities of some anticancer drugs can be well anticipated The toxicities of some anticancer drugs can be well anticipated
and hence be prevented by giving proper and hence be prevented by giving proper medications medications
Examples: Examples:
MES is MES is given to prevent hemorrhagic given to prevent hemorrhagic cystitis caused cystitis caused by by
cyclophosphamide cyclophosphamide
dexrazoxane dexrazoxane, is used to reduce the risk of , is used to reduce the risk of anthracycline anthracycline- -
induced induced cardiomyopathy cardiomyopathy
Drugs Used in Cancer Chemotherapy Drugs Used in Cancer Chemotherapy
Cytotoxic Cytotoxic gents gents
alkylating alkylating gents gents
antimetabolites antimetabolites
cytotoxic cytotoxic antibiotics antibiotics
plant derivatives plant derivatives
monoclonal antibodies monoclonal antibodies
Hormones Hormones
suppress suppress nat`l nat`l hormone hormone secr`n secr`n or antagonize hormone action or antagonize hormone action
Anll-cuncer drugs
lkylating lkylating gents gents
Contain chemical groups that covalently bind cell Contain chemical groups that covalently bind cell nucleophiles nucleophiles
Can form Can form carbonium carbonium ions ions
a carbon atom with 6 electrons highly reactive a carbon atom with 6 electrons highly reactive
react with react with - -H H
22
, , - -OH, OH, - -SH SH
bifunctional bifunctional compounds (2 reactive groups) compounds (2 reactive groups) cross cross- -linking linking
Targets: Targets:
G ; 1; 3; C 3 G ; 1; 3; C 3
D becomes cross D becomes cross- -linked linked
intra intra- - or inter or inter- -strand strand
decreased transcription, replication decreased transcription, replication
chain scission, so strand breaks chain scission, so strand breaks
inappropriate base pairing ( inappropriate base pairing (alkylated alkylated G with T) G with T)
S phase replication stops S phase replication stops G2 block G2 block
#ang 50.4
Cyclophosphamide Cyclophosphamide
Most common; also immunosuppressant Most common; also immunosuppressant
Prodrug Prodrug -- liver liver metab metab by CYP P450 by CYP P450
Oral or IV usually Oral or IV usually
DRs: nausea, vomiting, BMS, DRs: nausea, vomiting, BMS,
hemorrhagic cystitis hemorrhagic cystitis: ameliorated : ameliorated
with SH with SH- -donors donors MES MES
42.6 cyclophosph
itrosoureas itrosoureas
lso activated in vivo lso activated in vivo
lkylate lkylate D D toxicity toxicity
Lomustine Lomustine
Cisplatin Cisplatin
MO: MO:
Cl Cl- - dissoc`s dissoc`s reactive complex that reacts with H reactive complex that reacts with H
22
OO
interacts with D interacts with D
intrastrand intrastrand cross cross- -link (G with adjacent G O6) link (G with adjacent G O6)
denaturation denaturation D D
DRs: DRs:
nephrotoxic nephrotoxic
severe nausea/ severe nausea/vomimting vomimting, ameliorated with 5 , ameliorated with 5- -HT3 antagonists HT3 antagonists
ondansetron ondansetron (decreased gastric motility) (decreased gastric motility)
carboplatin carboplatin -- fewer above DRs, but more fewer above DRs, but more myelotoxic myelotoxic
ntimetabolites ntimetabolites
Mimic structures of normal metabolic molecules Mimic structures of normal metabolic molecules
inhibit enzymes competitively inhibit enzymes competitively Kill cells in S phase Kill cells in S phase
Three main groups: Three main groups:
folate folate antagonists antagonists
pyrimidine pyrimidine analogs analogs
purine purine analogs analogs
Folic cid nalogs Folic cid nalogs
Folic acid essential for Folic acid essential for synth synth purines purines, and , and thymidylate thymidylate
Folate Folate: : pteridine pteridine ring + PB + glutamate ring + PB + glutamate
In cells, converted to In cells, converted to polyglutamates polyglutamates then then
tetrahydrofolate tetrahydrofolate (FH (FH
44
) )
Folate Folate FH4 FH4 catalised catalised
by by dihydrofolate dihydrofolate
reductase reductase in 2 steps: in 2 steps:
Folate Folate FH2 FH2
FH2 FH2 FH4 FH4
FH4 serves as methyl FH4 serves as methyl
group donor (1 group donor (1- -C C
unit) to unit) to deoxyuridine deoxyuridine
( (dUMP dUMP dTMP dTMP), also ), also
regenerating FH2 regenerating FH2
Folic cid nalogs: MO Folic cid nalogs: MO
Methotrexate Methotrexate
Higher affinity for enzyme than does FH2 Higher affinity for enzyme than does FH2
additional hydrogen or ionic bond forms additional hydrogen or ionic bond forms
Depletion of FH4 in cell Depletion of FH4 in cell
depletion of depletion of dTMP dTMP
inhibition D synthesis inhibition D synthesis
Uptake through Uptake through folate folate transport system transport system
resistance through decreased uptake resistance through decreased uptake
Metabolites ( Metabolites (polyglutamate polyglutamate deriv`s deriv`s) retained for weeks, months ) retained for weeks, months
Pyrimidine Pyrimidine nalogs nalogs
55- -Fluorouracil Fluorouracil -- dUMP dUMP analog also works through analog also works through dTMP dTMP
synthesis pathway synthesis pathway
converted converted ~fraudulent nucleotide ~fraudulent nucleotide FdUMP FdUMP
competitive inhibitor for competitive inhibitor for thymidylate thymidylate synthetase synthetase
active site, but can`t be converted to active site, but can`t be converted to dTMP dTMP
covalently binds covalently binds thymidylate thymidylate synthetase synthetase
MO uses all 3routes MO uses all 3routes decreased D synthesis, decreased D synthesis,
also transcription/translation inhibition also transcription/translation inhibition
http://biotech.icmb.utexas.edu/botany/giIs/vdes.giI
Plant lkaloids: Plant lkaloids: Vinca Vinca lkaloids lkaloids
Vinca Vinca lkaloids: lkaloids: Vincristine Vincristine
Work at mitosis Work at mitosis
affects affects tubulin tubulin, therefore microtubule activity , therefore microtubule activity
prevention spindle formation prevention spindle formation OR OR
stabilize (~freeze) polymerized microtubules stabilize (~freeze) polymerized microtubules
arrest of mitosis arrest of mitosis
Other effects due to Other effects due to tubulin tubulin defects defects
phagocytosis phagocytosis//chemotaxis chemotaxis
axonal transport in neurons axonal transport in neurons
DRs DRs
numbness, tingling of the extremities, loss of deep tendon numbness, tingling of the extremities, loss of deep tendon
reflexes and weakness of distal musculature ~foot drop reflexes and weakness of distal musculature ~foot drop
and ataxia; alopecia (20), and ataxia; alopecia (20), opstipation opstipation, BMS is mild , BMS is mild
#ang 50.1
ntitumor gents Working through CeII SignaIIing
Binding Epidermal Growth Factor Binding Epidermal Growth Factor
Receptors Receptors Cell Cell Prolifileration Prolifileration
EGFR present on many solid tumors EGFR present on many solid tumors
Tyrosine Tyrosine- -kinase kinase type receptors type receptors
Ligand Ligand binding binding kinase kinase cascade cascade transcription factor transcription factor
synthesis synthesis
increased cell proliferation increased cell proliferation
metastasis metastasis
decreased apoptosis decreased apoptosis
Cells expressing EGFR resistant to Cells expressing EGFR resistant to cytotoxins cytotoxins; poor ; poor
clinical outcome predicted clinical outcome predicted
Trastuzumab Trastuzumab
~humanized mouse ~humanized mouse
monoclonal monoclonal b b useful in useful in
breast cancer patients who breast cancer patients who
overexpress overexpress HER2 HER2
binds HER2 binds HER2
membrane protein membrane protein
structurally similar to structurally similar to
EGFR EGFR
has integral tyrosine has integral tyrosine
kinase kinase activity activity
in breast cancer cells in breast cancer cells
DRs DRs
o BMS, o BMS,
http://www.gene.com/gene/products/inIormation/oncology/herceptin/images/moa.jpg