Cancer Chemotherapy New

8/12/2019 Cancer Chemotherapy New

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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.


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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


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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


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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


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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


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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


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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


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=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


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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


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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

Cancer Chemotherapy New

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