Download - Cancer Chemotherapy New
-
8/12/2019 Cancer Chemotherapy New
1/22
1
CANCER CHEMOTHERAPY (Renal Cancers)
Cancer is characterized by uncontrolled groth o! abnor"al cells#
Cancer cells do not respond to the normal processes that regulate cell growth, proliferation,
and survival, they can't carry out the physiologic functions of their normal mature cells.
$a"age to cellular $NA can result in "utation %cancer de&elo'"ent#
As normal cells
The cell cycle contain 4 phases (S, M, 1, !" each responsi#le for a different tas$
necessary for cell division.
1. %uring the first activity phase, the M phase, the cell
undergoes mitosis (cell division".
!. Then, the cell enters the first gap or resting phase 1.
%uring this the cell ma$es the en&ymes necessary for
% synthesis.). The synthesis of % occurs during the ne*t activity
phase called S phase.
4. fter that, the cell enters a second gap phase, resting !.
+ other proteins are synthesi&ed during this phase to
prepare for cell division during the M phase.
A!ter that-
. Continue to proceed through the cell cycle to divide again.
/. Mature into speciali&ed cells eventually die.
0. third resting phase o, proliferation of some normal cells under fine control to
#alance the loss of mature functional cells with the production of new cells.
-
8/12/2019 Cancer Chemotherapy New
2/22
CA**+,+CAT+ONO,ANT+CANCERA-ENT*
./A0YAT+N- A-ENT*
.) Nitrogen "ustards
1) Nitrosoureas
2) Al3yl sul!onates
4) Platinu" Coordination Co"'ounds
Most useful agents-Nitrogen "ustards
Cyclophosphamide (Cyto*an"
o fosfamide
Mechlorethamine
Melphalan (l$eran"
Chloram#ucil (eu$eran"
Secondary agents-Al3yl sul!onates
Thiopeta (Thiople*"
o 2varian cancer
o 3rinary Cancer
usulfan (Myleran"
o Chronic myeloid leu$emia
Ma5or nitrosoureas-
Carmustine (C3"
omustine (CC3"
Semustine (methyl CC3"
Poly!unctional Al3ylating $rugs Mechanis" o! Action
CC6+ T76+89:+T766S7
-
8/12/2019 Cancer Chemotherapy New
3/22
)
l$yl group transfer
o Ma5or interaction- l$ylation of %
8rimary % al$ylation site- 0 position of guanine (other sites as
well"
interaction may involve single strands or #oth strands (cross lin$ing,due to #ifunctional ;! reactive centers< characteristics"
o 2ther interactions- these drugs react with car#o*yl, sulfhydryl, amino,
hydro*yl, and phosphate groups of other cellular constituents
o These drugs usually form a reactive intermediate :: ethyleneimonium ion
Poly!unctional Al3ylating $rug Resistance
=ncreased a#ility to repair % defects
%ecreased cellular permea#ility to the drug
=ncreased glutathione synthesis
o inactivates al$ylating agents through con5ugation reactions (cataly&ed #y
glutathione S:transferase"
Phar"acological E!!ects Poly!unctional Al3ylating $rugs
=n5ection site damage (vesicant effects" and systemic to*icity.
To*icity-
o dose related
o primarily affecting rapidly dividing cells
#one marrow
= tract
nausea and vomiting within less than an hour:: with
mechlorethamine, carmustine (C3" or cyclophosphamide
6metic effects- CS
reduced #y pre:treatment with phenothia&ines orcanna#inoids.
o Cyclophosphamide cytoto*icity depends on activation #y microsomal en&yme
system.
7epatic microsomal 84> mi*ed:function o*idase cataly&es
conversion of cyclophosphamide to the active forms-
4:hydro*ycyclophosphamide
aldophosphamide
o Ma5or To*icity- #one marrow suppression
-
8/12/2019 Cancer Chemotherapy New
4/22
dose:related suppression of myelopoiesis- primary effects on
mega$aryocytes(#one marrow cells"
platelets
granulocytes one marrow suppression is worse when al$ylating agents are
com#ined with other myelosuppressive drugs and?or radiation (dose
reduction re@uired"
=f #one marrow suppression is severe, treatment may have to #e
suspended and then re:initiated upon hematopoietic recovery.
ong:term conse@uences of al$ylating agent treatment include-
ovarian failure (common"
testicular failure (common"
acute leu$emia (rare"
2ral +oute of dministration-cyclophosphamide (Cyto*an", melphalan (l$eran",
chloram#ucil (eu$eran", #usulfan (Myleran", lomustine (CC3,Cee3"
Cyclophosphamide (Cyto*an"- most useful al$ylating agent at present.
usulfan (Myleran"- specificity for granulocytes :: chronic myelogenous leu$emia
Nitrosoureas
o not cross reactive ( with respect to tumor resistance" with other al$ylating
drugs.
o onen&ymatic #y transformation re@uired to activate compounds.
o 7ighly lipid: solu#le:: crosses the #lood:#rain #arrier ("
useful in treating #rain tumors
o ct #y cross:lin$ing- % al$ylation
o
More effective against cells in plateau phase than cells in e*ponential growthphase
o Ma5or route of elimination-urinary e*cretion
o Steptozocin:
sugar:containing nitrosourea
minimal #one marrow suppression
effective in insulin:secreting islet cell pancreatic carcinoma and
sometimes in non:7odg$in's lymphoma
Other Al3ylating $rugs
CC6+ T76+89:+T766S7
-
8/12/2019 Cancer Chemotherapy New
5/22
8rocar#a&ine (Matulane"
o Methylhydra&ine derivative
o ctive in 7odg$in's disease (com#ination therapy"
o Teratogenic, mutagenic, leu$emogenic.
o Side effects-
nausea, vomiting, myelosuppression
hemolytic anemia
pulmonary effects
%acar#a&ine (%T=C"
o Clinical use-
Melanoma(cancer of muscle,#ones" 7odg$in's disease(lymphoid cancer"
soft tissue sarcoma
o Synthetic drugA re@uires activation #y liver microsomal system.
o 8arenteral administration
o Side effects-
nausea, vomiting, myelosuppression
Platinum Coordination Compounds
Cisplatin (Platinol)
o Clinical use-
Genitourinary cancers
testicular
ovarian
bladder
=n com#ination with #leomycin and vin#lastine- curative treatment for
nonseminomatous testicular cancer
Car#oplatin (less = and renal to*icityA with myelosuppressive
to*icity"- alternative to cisplatin
o =nhi#its % synthesisA cross:lin$ingA guanine 0 site
o 8latinum compounds- synergistic with other anticancer agents
o Site effects-
ma5or acute effect- nausea, vomiting
relatively little #one marrow effects
-
8/12/2019 Cancer Chemotherapy New
6/22
significant renal dysfunction (minimi&ed #y ade@uate
hydration?diuretics"
acoustic nerve dysfunction(hearing"
Al3ylating Agent To5icity
mechlorethamine, cyclophosphamide, carmustine- ausea and Bomiting (common"
2ral cyclophosphamide- ausea and Bomiting (less fre@uently"
Most =mportant To*ic 6ffect-one marrow suppression, leu$openia,
throm#ocytopenia
o secondary to myelosuppression ::
severe infection
septicemia
o hemorrhage
Cyclophosphamide (Cyto*an"-alopecia, hemorrhagic cystitis (may #e avoided #y
ade@uate hydration"
1/ANT+ META6O+TE (S phase, cell cycle specific"
Methotre5ate (MT7)
o Mechanism of ction- olic acid antagonist- acts at catalytic side of
dihydrofolate reductase
o 8olyglutamate- important in methotre*ate action
o Tumor resistance to methotre*ate-
decreased drug transport into the cell
CC6+ T76+89:+T766S7
-
8/12/2019 Cancer Chemotherapy New
7/22
0
altered dihydrofolate reductase en&yme :: lower affinity for
methotre*ate
decreased polyglutamate formation
@uantitative increase in dihydrofolate reductase en&yme concentration
in the cell (gene amplification, increased message"
o dverse effects-
one marrow suppression
%ermatologic
= mucosa
Adverse effects reversed by leucovorin (citrovorum factor)
eucovorin DrescueD may #e used in cases of over dosage or in
high:dose methotre*ate protocols
o 2ther uses-
Treatment of rheumatoid arthritis
=n com#ination with a prostaglandin- induces a#ortion
P8R+NE ANTA-ON+*T*
o /:Thiopurines (Mercaptopurine ;/:M8
-
8/12/2019 Cancer Chemotherapy New
8/22
=n acute leu$emia :: increased al$aline phosphatase, which
dephosphorylates thiopurines nucleotides
o dverse 6ffects-
oth mercaptopurine and thioguanine, given orally, are e*creted in the
urine.
/:M8 is converted to an inactive meta#olite, /:thioruric acid,
#y *anthine o*idase .
=n cancer (hematologic" chemotherapy, allopurinol is used to
inhi#it *anthine o*idase, to prevent hyperuricemia associated
with tumor cell lysis E*anthine o*idase inhi#ition #loc$s purine
degradation :: purines (more solu#le" are e*creted instead of
uric acid (less solu#le"F
use of allopurinol thus #loc$s acute gout and
nephroto*icity.
7owever, the com#ination of allopurinol and /:
mercaptopurine, #ecause of *anthine o*idase inhi#ition, can
lead to mercaptopurine to*icityA This interaction does not occur
with /:T.
PYR+M+$+NE ANTA-ON+*T*
o lurouracil (:3", normally given #y =B administration (oral a#sorption
erratic"
iotransformed to ri#osyl: and deo*yri#osyl: derivatives.
Mechanism of ction-
2ne derivative, :fluoro:!':deo*yuridine ':phosphate
(d3M8", inhi#its thymidylate synthase and its
cofactor,a tetrahydrofolate derivative, resulting in
inhi#ition of thymidine nucleotide synthesis.
nother derivative, :fluorouridine triphosphate is
incorporated into +, interfering with + function.
Cytoto*icity-effects on #oth + and %
Clinical 3se- Systemically :: adenocarcinomasA Topically- s$in cancer
lo*uridine (3%+"- similar to :3, used for hepatic artery infusion.
Ma5or To*icity- myelosuppression, mucositis.
o Cytara#ine (ara:C" =B administration
Mechanism of ction-S phase:specific antimeta#olite
iotransformed to active forms- ara:CT8, competitive inhi#itor
of % polymerase.
CC6+ T76+89:+T766S7
-
8/12/2019 Cancer Chemotherapy New
9/22
G
loc$s % synthesisA no effect on + or protein
synthesis
cytara#ine incorporated into + and % :: interfering with
chain elongation
Clearance- deamination (inactive form"
S phase specificity- highly schedule:dependent
Clinical 3se- almost e*clusively for acute myelogenous leu$emia
dverse 6ffects-
nausea
alopecia
stomatitis
severe myelosuppression
PANT A0AO+$*#
./&inca al3aloids
"Bin#lastin Bincristine-
Mechanis" o! action
=nhi#ition of tubulin 'oly"eraizationmitotic arrest leading to cell death.
Microtu#ule- :a hollow tu#ular structure composed of the protein tu#ulin that helps to maintain
the shape and movement of a living cell and the transportation of material within it.
To5icity
8hle#itis
9inblastinmore potent as "yelosu'ressant(s'inal cord su''ression)
9incristineneuroto*icity ("ainly 'eri'heral neuro'athy:consti'ation.
Clinical uses o! 9inblastin % 9incristine
-
8/12/2019 Cancer Chemotherapy New
10/22
Several pediatric tumors.
7ematological malignancies such as 7odg$in non 7odg$in lymphoma multiple
myeloma.
!:ta*ane family-
Eg. Paclitaxal ( al$aloid ester"
Mechanis" o! action o! Paclitaxal
Mitotic spindle poison.ind to microtu#ules sta#ili&ing them in polymeri&ed state
causing inhi#ition of mitosis cell division.
8ses o! Paclitaxal
dvanced ovarian metastatic #reast cancer
on small cell small cell lung cancer.
Ad&erse e!!ects o! Paclitaxal
The common triad
M depression ( neutropenia"
7ypersensitivity reactions, H of patients characteristic