ANTINEOPLASTIC DRUGS

Drugs mitigating side-effects: !!" #ar$ Tutt%e

Name #ec&anism
Pa%ifermin -Decrease t&e incidence 'f muc'sitis in &ig&-d'se c&em't&era() 'f &emat'%'gic ma%ignancies
-Recombinant keratinocyte growth factor (KGF)
-Induces proliferation of endothelial cells but N! hematopoietic cell lineages b"c no KGF-receptor
Ondansetr'n and Granisetr'n -Acts 'n c&em'rece(t'r trigger *'ne +CT,- 'f CNS as Serat'nin +./T0- Rece(t'r antag'nists c'ntr'% ACUTE emesis +'n%) 1 n't de%a)ed
emesis-
De2amet&as'ne -#orticosteroid anti-inflammatory Anti-emetic +'n%) 1 n't de%a)ed emesis-
A%$)%ating agents: T&e Nitr'gen #ustards +N't )'ur a3erage 4renc&5s LOL666-
Name Target Cancer #ec&anism Side effects P&armac'$inetics Resistance
$ll Nitrogen %ustards
-React with&
- 'ater
- (roteins
- Nuc%eic acids: GUANINE 7ases 'f DNA
#ross link ) especially difficult to repair
-#an produce secondary
leukemias
- *+ L'ss 'f c&'%ine
u(ta$e s)stem
(effects most N-
mustards)
8 Increased
9i'transf'rmati'n
oG%utat&i'ne :
!ripeptide
antio,idant which
protects against
R- by keeping
things in a reduced
state ) many of
these drugs need to
be o,idi.ed to be
acti/e
o#eta%%'t&i'nein :
%any cystine side
chains which ha/e
-0 ) react
/igorously with
alkylating agents
08 A%tered DNA re(air
#ec&%'ret&amin
e
-Good for %i;uid
tum'rs but not for
solid tumors because
its half life is short
-1esication
-If some leaks out of I1
administration2 will cause local
necrosis counteract with
hyposulfate
-1ery short half life
because it is
readily hydroly.ed
by water
-(arenteral
administration
#e%(&an -3etter at s'%id state
tum'rs
-4specially breast
cancer
- -#an be gi/en orally
--e/eral hour half
life
C)c%'(&'s(&am
ide
- -,idi.ed by li/er (567 to acti/e form
-$cti/e form is to,ic to li/er if it accumulates2 but it is
usually inacti/ated by breaking the N- ring to
nonto,ic form
-$cti/e form (phosphoramdie mustard) diffuses to
tissues including bladder
--ome is decomposed to to,ic metabolite ar'%ein
which can cause hemorrhagic cystitis
-8ess likely to produce
secondary leukemias
-/em'rr&agic c)stitis due to
decomposition to to,ic
acr'%ein in tissues
-!his is generally controlled by
hydration 9 dieresis
-Cardi'mi'(at&)
<=Trastu*uma9
-$ prodrug ) needs
to be o,idi.ed by
the li/er to be
acti/e
-L'ngest &a%f %ife 1
> &rs
-ral administration
%esna (%esne,) -4specially indicated for
iphosphamide2
-Necessary for those on #yclophosphamide who are
on anti-diuretics2 or cannot otherwise pre/ent
hemorrhagic cystitis by hydration 9 dieresis (kidney
problems)
- -
A%$)%ating agents: Ot&ers
NITROSOUREAS:
Carmustine ?
L'mustine
-CNS Cancers - -De%a)ed 9'ne marr'< su((ressi'n ) important to
remember if you are treating with multiple drugs as in
most cancer regimens ) don:t want bone '3#
trough:s to ha/e ;constructi/e interference< hella
low '3#s
Tem'*'%amide -Nitr's'urea-resistant
Ana(%astic
astr'c)t'ma
- - -
7usu%fan -#)e%'c)tic %eu$emia
since it is specific for
granulocytes
- -Pu%m'nar) fi9r'sis:
7usu%fan Lung -- -uspect
when chronic cough in cancer
patient
-
Cis(%atin -@ide s(ectrum& blood
and solid tumors
- A8 Litt%e effect 'n 9'ne marr'<
8 /ig&%) emetic
08 Ot't'2icit)
-
5+ Rena% t'2icit) (but pre/ented
with hydration"dieresis)
$mifostine - -Pre3ents rena% t'2icit) 'f Cis(%atin
-Reacts with cisplatin in non-cancer cells (especially
Kidney) that posses a%$a%ine (&'s(&atase (cancer
cells lack this)
- -3ecomes less
polar when reacted
with $( ) better
entry
$ntimetabolites& 4'%ic Acid Ana%'gs
Name Target Cancer #ec&anism Side effects P&armac'$inetics Resistance
#et&'tre2ate
(a =0F analog)
-%any cancers -Irre3ersi9%) in&i9its Di&)dr'f'%te Reductase +D/4R-
) part of the (urineB t&)mid)%ate s)nt&esis (at&<a)
+DNAB RNA-
-!rapped in cells as charged polyglutamate form2 helps
accumulate drug in target cells
-(roblem& also accumulates especially in
*+ Kidney damage
>+ 8i/er damage& since this is
natural storage center for
folate
?+ -e/ere mucositis
- *+ U(ta$e CB f'%ate
carrier s)stemC
(0owe/er growth of
cancer is retarded
since all cells need to
make =N$ to grow)
8 D/4R c'ntent :B
#utated D/4R
8euco/orin
(a !0F analog)
-@sed with
%ethotre,ate
-DrescueD 9'ne marr'< and gastr'intestina% muc'sa
ce%%s from methotre,ate since it d'es NOT re;uire
D/4R ) !0F is downstream of =0FR in the purine
synthesis pathway
- -
$ntimetabolites& P)rimidine Ana%'gs
.-4%ur'uraci% +.-
4U-
- -#eta9'%ite 4dU#P in&i9its t&)mid)%ate s)nt&ase2 an
en.yme in the !%(=N$ synthesis pathway2 9ut is
(''r at d'ing t&is if gi3en a%'ne
-If gi3en <it& Leuc'3'rin (!0F analog)2 forms a ?-
member comple, with thymidylate synthase2 t&at
in&i9its 3irtua%%) ALL 'f t&e en*)me
- -
.-4%u'r'de'2)8
+4UdR-
-#etasteses fr'm
9'<e% cancer ONLE
-#ommitted to =N$ synthesis N8A (Not RN$) - -Direct infusi'n
int' &e(atic arter)
Gemcita9ine -4irst-%ine drug f'r
(ancreatic cancer
-8ung"bladder also
-Inhibits ri9'n'c%eutide reductase
-$cts as a c&ain terminat'r
-8ike 6-F@2 substitutes hydrogen for fluorine at a gi/en #
- -
$ntimetabolites& Purine Ana%'gs
>-T&i'guanine -$cute leukemias
-#%8 (wiki)
*+ %etaboli.ed /ia the (urine -al/age (athway& /GPRT (0ypo,anthine-guanine phosphoribosyltransferase)
functions in normal cells to sal/age damaged purines+
- 3y pseudofeedback interference with purine biosynthesisB interferes <it& t&e s)nt&esis 'f guanine
nuc%e'tides ('iki)
-$s a minor secondary pathway2 is con/erted to %ercaptopurine (con/erted to $!(2 G!(2 Gout)
>-#erca(t'(urine - *+ %etaboli.ed /ia the (urine -al/age (athway& /GPRT (0ypo,anthine-guanine phosphoribosyltransferase)
functions in normal cells to sal/age damaged purines+
- #on/erted to thio-I%( which in&i9its (r'ducti'n 'f ATP and GTP
>+ #on/erted to !hiouric acid by Banthine o,idase which also functions in the production of uric acid and gout
- $ concern because gout is a side effect of many cancers (especially leukemias"lymphomas) and ppl may be
taking $llopurinol (,anthine o,idase inhibitor) to pre/ent gout =osage will need to be adCusted
A%%'(urin'% -Not a cancer drug -@sed by some ppl with leukemia"lymphoma
-Interacti'n <it& >-#erca(t'(urine since it in&i9its
'n Fant&ine '2idase
- -
A*it&r'(ine -Not a cancer drug -Is an immunesuppressi/e prodrug used in pre/enting
organ reCection
-Reduced by Glutathione to make D-%ercaptopurine
- -
Genera% side effects t' anti-ne'(%astics De3e%'(ment 'f mu%ti-drug resistance
*+ 3one marrow suppression
>+ %ucositis (ulcers)
?+ $lopecia (hair loss)
5+ Infection resistance E
6+ Infertility
D+ !eratogen
F+ @ric acid2 K92 (2 #a>9 G
H+ H+ Nausea2 /omiting2
anore,ia
*+ @ptake of drug
>+ -ignal transduction to nucleus
?+ 4,spression and processing of drug pump
5+ %ature %=R-* (multiple drug resistance) pump eliminates a broad spectrum of
antineoplastics
Anti9i'tics ? A%$a%'ids: =o,orubicin (I =aunorubicin)2 =actinomycin2
3leomycin
J>77K %ark !uttle
Name Target Cancer #ec&anism Side effects P&armac'$inetics
D'2'ru9icin -'ide spectrum& included in
almost half of drug
combinations
-Intercalates =N$ bases and in&i9its DNA
and RNA ('%)merases
*+Cardi't'2icit) (especially w"!rastu.uman)
$cute& $rrhythmias
#hronic& =igitalis-resistant congesti/e heart
failure (use =e,ra.o,ane)
8ifetime dose dependent ) >7L of patients
recei/ing 667 mg"m>
>+-e/ere alopecia
?+(otent /esicant
-
=e,ra.o,ane - -Pr'tecti'n against D'2'ru9icin-induced
c'ngesti3e &eart fai%ure 9) ma$ing 4e
0?

una3ai%a9%e to generate R-2 damaging
heart
- -
#it'tic S(ind%e P'is'ns
Ginca a%$a%'ids -3road spectrum -(re/ent assem9%) 'f mit'tic micr'tu9u%es - -
Gincristine -Neuroto,icity (dose limiting)
-
-
Gin9%astine -3one marrow suppression -
Pac%ita2e% -Cis(%atin-resistant '3arian
cancer
-ther cancers now too- broad
spectrum
-(re/ent disassem9%) 'f mit'tic
micr'tu9u%es
-3one marrow suppression
-0ypersensiti/ity in *->L of patients
pre-treat with antihistamines and steroids
-
T'('is'merase in&i9it'rs
Irin'tecan +a
Cam(t't&ecin-
-#etastatic c'%'recta% cancer
c'm9ined <it& %euc'3'rin
and .-4U
-#uts =N$ by in&i9iting T'('is'merase I *+=iarrhea (immediate 9 delayed)
=elayed is se/ere ) electrolyte imbal
-3iliary e,cretion
$dCust dosage if hepatic
disease
Et'('side and
Teni('s'side
- -#uts =N$ by in&i9iting T'('is'merase II >+0igh incidence of secondary leukemias
beginning > years after treatment
?+=rug allergy
5+=ecrease dosage in kidney failure
-!enipososide is e,tensi/ely
metaboli.ed
/'rm'na% t&era()
Tam'2ifen
(Nol/ade,)
-Ne<: reduce incidence 'f
9reast cancer in at-ris$
<'men:
*+ 679 years old
>+ Family history
?+ 0ealth history (abnormal
biopsy)
5+ First child at M>Kyo
6+ First period N*>yo
-4strogen receptor (4R) antagonist
#an be a sur/i/al signal"growth factor of
cancer cells
nly useful in cancer cells e,pressing 4R"(R
- -
-
Amin'g%utet&imid
e
- -Inhibit estrogen synthesis - -
4%utamide -C'm9ined t' treat (r'state -$n antiandrogen - -
cancer Leu(r'%ide -Gonadotropin-releasing hormone (GnR/)
$K$ 8euteini.ing-releasing hormone (L/R/)
ag'nist
-4ncourages F-0 and 80 release from
anterior pituitary
- -
Antine'(%astics: Signa% Transducti'n Pat&<a) #'du%at'rs
Rec(t'r T)r'sine Hinase In&i9it'rs !!" #ar$ Tutt%e
Name Target Cancer #ec&anism Side effects
Imatinin #es)%ate
+G%ee3ec-
-C&r'mic #)e%'gen'us Leu$emia
+C#L-
*+In&i9its 7CR=A7L- the constituti/ely acti/ated tyrosine
kinase produced by K&>> (hiladelphia chromosome
translocation
87%'c$s @/C (r'%iferati'n
08In&i9its C)(0AI c)t'c&r'me PI.! en*)me
-
Gefitini9 (Iressa) -N'n-sma%% ce%% %ung cancer
-US: 7est in fema%e n'n-sm'$ers
-Ja(an: >K <it& NSCLC &a3e EG4R
mutati'ns susce(ti9%e t' Gefitini9
-In&i9its EG4R (4pithelial Growth Factor Receptor) -
Pr'teas'me In&i9it'rs
7'rte*'mi9 (#elcade) -#u%ti(%e m)e%'ma -In&i9its (r'te's'me& the maCor protein metaboli.ing en.yme
in cells
- Important for cell cycle progression by controlling entry into
maCor phases of cell cycle (G*2 -2 G>2 %)
- 3uild-up of damaged proteins results in cell death
-
#'n'c%'na% Anti9'd) T&era()
Trastu*uma9
(0erceptin)
-
-
-An anti-/ER Rece(t'r Anti9'd)
-'orks by inhibiting 04R>-R growth signaling properties
-4,pressed in ?7L of breast cancer patients and associated
with rapid progression of breast cancer
A8 Se3ere a%%ergic reacti'ns
8 Cardi'm)'(at&) <&en c'-administered <it&
d'2'ru9icin 'r c)c%'(&'s(&amide
- Fi/e-year followup& >"? of women had increased
heart function but still not to pre-treatment le/els
- Finnish study& #ardio/ascular to,icity may be
decreased by administering trastu.umab before
do,orubicin instead of concurrently
Ritu2ima9 (Ritu,an) -N'n-/'dg$ins L)m(&'ma -Targets CD! +7-ce%%s- - Se3ere reacti'nsB e3en ana(&)%a2is
Ceru2imi9 (4rbitu,) -EG4R-e2(ressing c'%'recta%
carcin'ma
-Targets E(iderma% Gr'<t& 4act'r Rece(t'r +EG4-R- A8/)('tensi'nB (&ar)ngea% edema 'n infusi'n
8S$in ras&es +P&'t'sensiti3it)-
7e3aci*uma9 ($/astin) -4irst-%ine treatment f'r metastatic
c'%'recta% cancer
-C'm9ined <it& irnitecanB .-4U and
%euc'3'rin
-7inds t' 3ascu%ar end't&e%ia% gr'<t& fact'r +GEG4- and
(re3ents 3ascu%ari*ati'n 'f tum'rs
-
A8Pr'9%ems <it& <'und &ea%ing
8Gastr'intestina% fistu%a f'rmati'n