1. Anti neoplastic Agents
Anti neoplastic agents used for the treatment of cancer
Neoplasm (in Greek, ‘neo’ means ‘new’ and ‘plasm’ means
‘formation 'refers to a group of disease caused by several
agents - namely, chemical compounds and radiant energy.
Cancer is characterized by abnormal and uncontrolled
division of cells, which produce tumors and invade adjacent
normal tissues.
Often, cancer cells separate themselves from the primary
tumours and carried by lymphatic system, reach distant sites
of organs, where they divide and form secondary tumours
(metastasis)
Cancer is classified according to the tissues and type of cells
in which new growth occurs.
2. 1. Carcinoma: Malignant tumours derived from epithelial cells.
2. Sarcoma : Malignant tumours derived from connective
tissue
3. Lymphoma and leukemia: Malignancy derived from
hematopoietic (blood -forming) cells
4. Germ cell tumour: tumours derived from totipotent cells.
1. Blastic tumour: A tumour (usually malignant ) that
resembles an immature or embryonic tissue. Many of these
tumours are most common in children
3. Treatment of cancer includes surgical intervention , radiation, immunotherapy, and
chemotherapy using neoplastic drugs.
Some type of tumours are currently treated first with chemotherapeutic agents.
Cancer chemotherapy is generally non – specific- means drugs kill not only cancerous
cells but also normal cells.
Special strategies developed to increase the potential of destroying cancerous cells and
lessening toxic effects on normal tissue.
CLASSIFICATION
1) Alkylating agents
i) Nitrogen mustard:
Mechlorithamine Melphalan Chlorambucil
Estramustine Uracilmustard Cyclophosphamide
Ifosphamide
6. Alkylating agents
Chemotherapeutic alkylating agents have the common
property of becoming strong electrophiles through the
formation of carbonium ion intermediates, which in turn react
with nucleophilic moieties of the target molecule(DNA).
It acts by transfer of alkyl groups to biologically important
constituents such as amino , sulfhydryl or phosphate group
whose function is then impaired.
Under physiological condition, alkylating agents are positively
charged and they react with negative or high electron density
region.
7. Alkylating agents known to react with DNA, RNA and
protein their reaction with DNA is believed to be
most important.
Alkylating agents act by alkylation on nucleophilic site i.e.,
In DNA 7- nitrogen atom of guanine is particularly
susceptible to form covalent bond with alkylating agents.
nu – H + Alkyl – y alkyl – nu + H + + Y -
8. Meclorethamine
Meclorethamine Hcl occurs as hygroscopic leaflets – very
soluble in water
Dry crystals stable at room temp up to 40 0 C.
Very irritating to mucous membranes and harmful to eyes.
It is supplied in rubber stoppered vials containing mixture
of Meclorethamine Hcl and sodium chloride.
It is diluted with 10 ml of sterile water immediately before
injection in to a rapidly flowing i.v infusion.
Intra cavity inj sometimes given to control malignant effusion
2HC N
CH2CH2Cl
CH2CH2Cl
2,2' - Dichloro -N- methyl diethyl amine
9. Aziridium ion formed from Meclorethamine in body
fluids is highly reactive.
It acts on various cellular components within mins of
admn.
Less than 0.01% recovered unchanged in the urine, but
more than 50% is excreted a inactive metabolites in the
first 24 h.
10. Med uses
Meclorethamine is effective in Hodgkin’s disease.
Prescribed in combination with other agents
Combn with vincristin(Oncovin), procarbocin and prednisone ,
known as MOPP regimen- consider treatment of choice.
Lymphomas and mycosis can be treated with Meclorethamine
O
CH3 N
CH2CH2OH
CH2CH2OH
CH2NH2
CH3 N
CH2CH2Cl
CH2CH2Cl
Ethylene oxide N-metyl diethanol amine Mechlorethamine
SOCl2
Synthesis
12. CYCLOPHOSPHAMIDE
O
P
HN
O
(ClH2CH2C)2
.H2O
Its monohydrate form is low melting solid
Very soluble in water
Supplied as 25 and 50 mg white tablets
As powder (100,200, or 500 mg ) in sterile
vials
For reconstitution 5ml/100mg of sterile
Water for Inj USP added
Oral dose of CYCLOPHOSPHAMIDE 90%
bioavailable with 8% first pass loss.
It must be metabolised by liver microsomes
to become active.
13. Among the metabolites, PHOSPHAMIDE mustard has anti
tumour activity and acrolein is toxic to urinary bladder.
Acrolein toxicity decreased by i.v. or oral admn of sod. Salt
of 2- mercapto ethane sulfonic acid (mesna)
Med uses
1.CYCLOPHOSPHAMIDE has advantages over other
alkylating agents – active orally and parenteral and given in
fractionated doses over prolonged periods.
14. 2. Active against multifull myeloma of children,
3. In combination with other chemotherapeutic agents,
has given complete remissions and even cures in
Burkett’s lymphoma and acute lymphoblastic
leukemia(ALL) in children.
Toxic effects
1. Alopecia and nausea and vomiting
2. Leukopenia
3. Sterile haerrhagic cystitis
4. Gonadal suppression
16. 2mg tab available for oral administration as solution.
Oral absorption is erratic and incomplete with absolute
bioavailability ranging from 25 to 89%
A preparation kit is provided for parenteral formulation
It contains 100mg Melphalan , which is dissolved in 1 ml
acid –alcohol solution and then combined with final diluents
containing 108 mg of dipotassium phosphate , 5.4 ml of
propylene glycol , and sterile water for injection USP . This
prepn should be used promtply.
There is no significant first-pass effect wtih melphalan but
drug is gradually inactivated by non enzymatic hydrolysis to
monohydroxy and dihydroxy derivatives.
17. Elimination is biphasic, with half-lives of 6 to 8 min
and 40 to 60 min
Med Uses
1. Active against multiple myeloma
2. Also active against breast, testicular and ovarian
carcinoma
Toxicity
1. Hematological – blood count must be followed
carefully
2. Nausea and vomiting infrequent
3. Alopecia
18. Chlorambucil
N
ClH2CH2C
ClH2CH2C
(CH2)3COOH
Soluble in ether and aqueous alkali
Its oral absorption is efficient and reliable
Sugar coated 2mg tablets are supllied
It acts most slowly and is the least toxic of any mustard
derivative in use.
It is indicated especially in the treatment of CLL and
primaryglobulinemia
Other indications are lympho sarcoma and Hodgkin’s
diseases.
19. Many patients develop progressive, but reversible
lymphopenia during treatment
Most patient also develop a dose related and rapidly
reversible neutropenia
For these reasons, weekly blood counts are made to
determine the total and differential leukocyte level
The Hemoglobin levels are also determined for
monitoring both toxicity and efficacy
20. BUSULPH
AN
CH3SO2(CH2)4 O SO2 CH3
Synthesis
HO (CH2)4 OH + 2CH3SO2Cl
CH3SO2 O (CH2)4OSO2CH3
Occurs as crystal and soluble in acetone and alcohol
Although practically insoluble in water, it slowly dissolves
on hydrolysis
Stable in dry air
It is supplied as 2 mg tablets
Well absorbed orally and metabolized rapidly
Much of the dugs undergoes a process known as “sulphur
stripping” in which thiol compounds such as glutathione or
cysteine results in loss of two equivalents of
methanesulphonic acid and formation of a sulphonium
intermediate involving the sulphur atom of the thiol.
21. Such sulphonium intermediates are stable in-vitro ,
but in-vivo they are readily converted into
metabolite, 3-hydroxy thiolane -1,1-dioxide.
Oral dose of busulfan are well tolerated
Absorption has zero order kinetics
The half life is 2.1 to 2.6 hours
22. Med Uses
Treatment of Granulocytic leukemia
Used for bone marrow transplantation in patients
with various leukemia
Toxicity
Depletion of thrombocytes may lead to
haemorrhage Blood count must be checked at least
weekly
Rapid destruction of granulosides
23. THIOTEPA
N P N
N
S
Tri-(1-aziridinyl) phosphine sulfide
White powder and water soluble
Suplied in vials containing 15mg of thiotepa, 80mg
of NaCl and 50g of NaHCO3
Sterile water used to make an isotonic solution
24. Both vials and solution must be stored at 2-8o C and
this solution may be stored 5 days without loss of
potency
Thiotepa blood levels decline in a rapid biphasic
manner
It is converted into TEPA by oxidative desulferization ,
and TEPA levels exceed those of thiotepa 2 hours
after admn
Aziridine metabolism also occurs with liberation of
ethanolamine
25. Med Uses
Tried against many type of cancer, most
consistent result obtained in breast, ovarian,
and bronchogenic carcinomas and malignant
lymphomas
It is also used to control intra cavity effusion ,
resulting from neoplasms
Toxicity
Highly toxic to bone marrow and blood counts
are necessary during therapy
26. Antimetabolites
Antimetabolites –Compounds prevent biosynthesis or use of normal
cellular metabolites. Chemical substances that take part in cellular
metabolite known as metabolites
Antimetabolites exert their action by acting as false precursor for
enzymes.
Many Antimetabolites- enzyme inhibitors. These drugs are
usually structural analogues of normal body metabolite, derived
from incorporating one or two iso- steric group or other structural
changes of metabolites
Structural modification of these metabolites may be on the
pyrimidine ring
27. Posisble MOA :
1.Inhibition of kinase or enzyme involved in
biosynthesis of pyrimidine
2.Incorporation into DNA or RNA leading to
miscoding
3.Inhibition of polymerase
29. Yellow crystal of monohydrate, Poor water solublity
Dissolves in dilute alkali but undergoes decomposition. Supplied as 50 mg tab
Inj formulation of vials contains 500mg sod salt of 6-mercaptopurine,which is
reconstituted with 48.5 ml of water for inj
It is not active until it is anabolized to the phosphorylated nucleotide. In this
form it competes with endogenous ribonucleotide for enzymes that convert
inosinic acid into adenine- and xanthine based ribonucleotide
Futher more, it is incorporated into RNA , where it inhibits further RNA
synthesis.
One of its main metabolite is 6-methyl mercaptopurine ribonucleotide ,
which is also a potent inhibitor of the conversion of inosinic acid to purines
Poor absorption, low bioavailability, first pass metabolism by liver and has
oral absorption
30. Peak plasma levels reached 2h after ingestion
It is metabolised by S- methylation followed by 8-
hydroxylation
It also oxidised to 6- thiouric acid
Tolerated dose varies with individual patients
Medicinal Use
1. Primarily treating acute leukemia, Children respond better
than adults
Toxic effect
1. Leukopenia
2. Thrombocytopenia and bleeding occurs with high dose
31. THIOGUANINE
HN
N
N
H
N
SH
2-AminoPurine -6-thiol
H2N
Supplied as 40 mg tab
Oral thioguanine poorly absorbed
Inj form is supplied in 75 mg vials
It is reconstituted by adding 5ml NaCl for inj USP
It is converted by hypoxanthine guanine phosphoribosyl
transferase into nucleotide form that inhibits a number of
reaction in DNA and RNA synthesis
Cross- resistance exist between thioguanine and
mercaptopurine
32. Med Use
1.Treating acute leukemia especially in
combination with cytarabine
Toxic effects
1.Bone marrow depression
2.Leukopenia
3.Thrompocytopenia
4.bleeding
33. PRIMIDINE ANALOGUES
1.Flurouracil
HN
N
H
F
O
O
5-Fluro-2,4-pyrimidinedione
Synthesis
Supplied in 10ml ampuls containing 500mg in water for inj
Stored at room temp and protected from light
It is potent inhibitor of thymidylate synthetase
It is also converted into flurouridine triphosphate, which is
incorporated into RNA and DNA
Plasma levels erratic after oral admn and high after parenteral
dosing
Extensively metabolised in the liver and main metabolite is
dihydrofluorouracil
Most of admnd dose is excreted in urine as alpha –fluoro-beta-
alanine
HN
N
H
F
O
O
5-Fluro-2,4-pyrimidinedione
HN
N
H
F
O
O
2,4-pyrimidinedione
CF3OF
Fluorination
34. Med Uses
1. Effective in palliative management of carcinoma of the breast,
colon, pancreas, rectum, and tomach in patients who can not
cured by surgery or other means
2. Topical formn used for the treatment of premalignant
keratoses of the skin and superficial basal cell carcinomas.
Toxic effects
1. Parenteral admn produces –Leukopenia
2. GI Heamorrhage
3. Stomatitis, Esophagopharyngitis, diarrhea, nausea , vomiting
4. Alopecia and dermatitis
5. Topical admn contraindicated in patients develop
hypersentivity
6. Prolonged exposure to ultraviolet radiation may increase the
intensity of topical inflammation reactions
35. H
H
CH2OH
OH H
H H
O
HN
N
O
F
O
FLOXURIDINE
Supllied in 5ml vials containing 500mg of floxuridine as sterile powder
and reconstitution by addition of 5ml sterile water and resulting solu stored
under refrigeration for NMT 2 weeks
It is prodrug of 5- Fluorouracil and freely soluble in water than 5-
Fluorouracil
It is admsd by continuous regional intra arterial infusion
When given in this manner , it has significant advantages over
Fluorouracil
Metabolically deoxy sugar moiety of floxuridine cleaved to give 5-
Fluorouracil
Med Use
Gastro intestinal Adenocarcinoma
36. CYTARABINE
H
H
CH2OH
OH H
H OH
O
HN
N
O
NH2
1-Beta-D-Arabinofuranosylcytosine
It is pyrimidine antimetabolite in which sugar has modified
It is supplied as freeze dried solid in vials containing 100 or
500mg
It is reconstituted with sterile water containing 0.9% benzyl
alcohol to give 20mg /ml cytarabine
Solution may be stored at room temp for 48 h
37. N
N N
N
NH2
CH2 N CONHCH(CH2)2COOH
CH3 COOH
H2N
METHOTREXATE
MOA: Sequential action of deoxycytidine kinase anabolizes cytarabine to
triphophorylated nucleotide, which acts as competitive inhibitor of DNA
polymerase, after incorporation into DNA chain leads to miscoding
It is specific the S-Phase of the cell cycle
Med Uses
1. Treatment of acute leukemia, chronic myelocytic leukemia, meningeal
leukemia, acute lympholytic leukemia (ALL) and chronic lympholytic
leukemia (CLL)
39. It is isolated as monohydrate as yellow solid
Soluble in alkali solution, but decompose in them
It is supplied as 25 mg tab and in vials containing either 5
or 50 mg of methotrexate sodium in 2ml of solution
5mg sample contains 0.9% benzyl alcohol as preservative
50 mg sample contains 0.9% benzyl alcohol , 0.26%
sodium chloride and sodium hydroxide to give pH 8.5
A preservative –free lyophilized preparation is
recommended for intra thecal admn to prevent or treat
tumour cells in CNS
40. After oral admn , it is rapidly but incompletely absorbed
Approximately 50 to 60% of the absorbed drug is bound
to plasma proteins.
Cytotoxic levels are found in cerebrospinal fluid when
high doses of methotrexate given
Most of the drug given is excreted in the urine
unchanged.
Plasma level decay is biphasic or possibly triphasic
41. Methotrexate binds tightly to dihydroflolate
reductase, blocking the reduction of
dihydrofolate to tetrahydrofolate- active form of
coenzyme.
It is specific for the S phase of cell cycle
Methotrexate undergoes polyglutamation
intracellularly, forming a pool of compounds that
is retianed for months
Rsistance to methotrexate develops by
increasing dihydroflolate reductase, which
results from gene amplification or by defective
transfort into tumor cells
42. Med
MMed Uses
Uses
1. It was the first drug to produce substantial remissions in
leukemia and treatment of lymphocytic leukemia and ALL
2. Used in the treatment and prophylaxis of meningeal
leukemia
3. Used in combination chemotherapy for palliative
management of breast cancer , epidermis cancers of head
and neck and lung cancer
4. It is also used against severe disabling psoriasis
Toxicities
Toxic effects
1 Ulcerative stomatitis, leukopenia, and abdominal distress
2. Renal failure in some patients. This condition is thought to
be result from crystallization of the drug or its metabolites in
43.
AZATHIOPRINE
N
N N
H
N
S
N
N
H3C NO2
It is supplied as 50 mg tab
Injectable salt available in 20 ml vials containing 100mg of
Azathioprine
Well absorbed when taken orally
It is converted extensively to 6- mercaptourine
44. The main indication of Azathioprine is as an
adjunct to prevent the rejection of hetero
transplants
It is contraindicated in patients who show
hypersensitivity to it
Toxic effects
1.Hematological disorder expressed as leukemia ,
anemia and Thrombocytopenia
2. Should not be taken with Allopurinol
45. ANTICANCER ANTIBIOTICS
Nine different antibiotics or their semisynthetic analogues are established clinical
anticancer agents , and other anibiotics under going clinical development
Some of these agents approved recently, however others are known for long time
1. Dactinomycin ( actinomycin D) (1940, Walksman)
2. Plicamycin ( Aureolic acid) (1962) (Mithramycin)
3. Actinomycins
4. Bleomycins
5. Mytomycin C
6. Doxorubicin
Antracyclines
7. Doxorubicin
8. Daunorubicin
9. Idarubicin
10. Carminomycin
Actinomycins comprise large no of closely related structures. All of them contains
chromophore- a substituted 3- phenoxazone-1,9- dicarboxylic acid known as
actinomycin
46. Anthracycline
Antracyclines –large and complex family of
antibiotics
Occur as glycoside of anthracyclinone
Glycosidic linkage usually involves 7-hydroxyl
group of the anthracyclinone and beta isomer
of sugar with L- configurations
Because of the conjguated anthraquinone
nucleus , the anthrayclines –reddish in color
and impart red color to the urine of the patient
47. MOA
anthraquinone nucleus of the anthracyclines intercalate
with DNA ,which leads to single and double stranded DNA
breaks
In addition , anthraquinone is also capable of generating
reactive oxygen species such as hydroxy radical (-OH)
and super oxide radical anion(-O – O)-
These free radicals may produce destructive effect
upon the cell which may include damage of DNA.
Generation of free radicals leads to cardio toxicity- a
major side effect of anthracyclines
49. DAUNORUBICIN
Obtained from fermentation of Streptomyce peucetiuss
Hcl salt red crystalline powder, soluble in water and alcohol
Available as lyophilized powder in 20mg vials, in this form
stable at room temp, but after reconstitution with 5 to 10ml
sterile water it should be used within 6 h
A new liposomal formulation of Daunorubicin known as
DaunoXome, is in phase two clinical trials
Significantly reduced toxicity, including cardio toxicity has
been claimed for it
Long terminal plasma half life of Daunorubicin results from
extensive tissue binding.
It is readily metabolised to Daunorubicinol by reduction of
its 13-keto group. This metabolite one-tenth as active as
Daunorubicin
Drug and its metabolite eliminated by hepatobiliary excretion
50. MOA:
A no of cellular lesions may contribute to the
antitumor activity of Daunorubicin
It intercalates into DNA and RNA and inhibit the
ligase activity of topoisomerase II
Redox cycling of quinone fuctionality generates
hydroxyl and superoxide radicals, which
peroxidize lipids and damage cellular membranes
This effect may produce cardiotoxicity because
heart cells relatively deficient in antioxidant
defenses
51. Usual dose of admn is 30 to 45mg /m2
It is admnd i.v taking care to prevent extravasation
Med Use
Treatment of acute lymphocytic and granulocytic leukemia
Toxic effects
Bone marrow depression
Stomatitis
Alopecia
And GI disturbances
At higher dose cardiac toxicity may develop
Severe and progressive congestive heart failure may follow initial
52. DOXORUBICIN (Adriamycin)
Obtained from cultures of Streptomyces peucetius
Orange red color needles are soluble in water and alcohols
Supplied as freeze dried powder in two different sizes: 10 mg plus 50 mg
of lactose USP and 50 mg plus 250 mg of Lactose USP
These amounts are reconstituted with 5 and 25 ml respectively, of NaCl
inj USP
After admn it rapidly distributed to body tissues, with about 75% of it
binding to plasma proteins
It is extensively metabolised and eliminated primarily as glucoronide
conjugates of the parent aglycone or 13-hydroxyl reduction product,
doxorubicinol
Disposition and elimination can be explained by two- comparment or a
three compartment model
Liposome- encapsulated doxorubicin (LED) is available in several
formulation for clinical trials
Dose : 60 to 75 mg by i.v at 21- day interval
MOA: Similar to those described for daunorubicin
53. Med Uses
Combination therapy with variety of other reagents is being
developed for specific tumors
Toxicity
Mylosupptression and cardio toxicity
Bone marrow depression, primarily of leukocytes
Red blood cells and platelets also maybe depressed, so careful blood
counts essential
Acute left ventricular failure
Use to produce regression in acute leukemias, Hodgkin’s disease and
other lymphomas, Wilms tumor, neuroblastoma, soft-tissue, and bone
sarcomas, breast carcinoma, transitional cell bladder carcinoma
Cardiomyopathy and congestive heart failure may be encountered several
weeks after discontinuing use of Adriamycin
54.
Toxicity augmented mainly by impaired liver function, because this site of
metabolism
Evaluation of liver function is by conventional laboratory is recommended
before individual dosing
IDARUBICIN HCl
HCl salt formulated in single – dose vials containing 5 mg or 10 mg of orange
lyophilized powder and is reconstituted with 5 or 10 ml NaCl for inj
These solu stable atleast 7 days under refrigeration
Admn is i.v , with care taken to avoid extravasation because of the potent
vesicant action
It differs from daunorubicin by lack of methoxy group
Like Daunorubicin , it intercalates DNA and inhibits topoisomerase II
55.
Med Uses
1. I.V Idarubicin is approved for therapy of acute nonlymphocytic leukemia
in combination with Cytarabine
2. Active against blast phase of chronic myelogenous leukemia
Toxicity
1. Its dose limiting toxicity is Myelosuppression
2. Leukemia
3. It appears to be less cardiotoxic than doxorubicin and daunorubicin
BLEOMYCIN SULFATE
Bleomycin sulfate – mixture of cytotoxic glycopeptides isolated from a
strain of Streptomyces verticillus
Main component is bleomycin A2 (less than 65%) and bleomycin (less
than 20 to 30 %)
It is whitish powder , readily soluble in powder
Occurs naturally as blue copper complex, but it removed later in
formulation
56. It is supplied in ampuls containing 15 uits of sterile bleomycin
sulfate
Bleomycin unit is based on inhibitory activity against
Mycobacterium smegmatis in culture
Bleomycin sulfate is reconstituted by dissolution in 1 to 5 ml of
sterile water, or normal saline for Inj
It undergoes rapid initial distribution with half life 10 to 20 min,
followed by elimination half- life of 2 to 3 h
It is inactivated readily in liver and kidney and excreted in urine
MOA:
Involves binding to DNA followed by single or double –strand
cleavage Transfer RNA also may be cleaved
These cleavage caused by active oxygen species that are
generated in a stepwise process from bleomycin –iron-oxygen
complexes
The process is cell specific, with main effect in the G2 and M
57. Med Uses
Palliative treatment of squamous cell carcinomas of the head and
neck, esophagus, skin, and cervix and vulva
Also used agaist testicular carcinoma , especially in combination
with cisplatin and vinblastine
Toxic effects: Mainly occurs in skin and lungs
1. Bone marrow depression
2. Pulmonary fibrosis
3. Toxicity in mucous membrane
4. Anaphylactoid reactions are possible in lymphoma patients
Dose;
0.2 to 0.50 units /kg given i.v , I.M or subcutaneous once or twice
weekly
59. Semisynthetic derivative of podophyllotoxin and supplied in 5-mL ampuls
containing
20 mg/rnL of the drug pIus 30 mg of benzyl alcohol. 80 rng of polysorbate ,
650mg of polyethylene glycol and absolute alcohol.
This mixture is diluted with either 5% dextrose or saline to give a final
concentration of 0.2 or 0.4 mg/mL
Etoposidc also is supplied as 50-mg capsules which also contain sorbitol.
They must be stored at 36 to 46°F.
The pharmacokinetics of etoposidc fit a two-compartment model. A terminal half-
life of 7 hours is independent of the dose and method of administration.
The primary metabolites found in plasma are picro hydroxy acids and picro
lactone
the major urinary metabolite is 4‘-demethylepipodophyllic acid. Oral
bioavailability is about 50 %
Elimination half-fife is 4 to II hours.
60. MOA:
Etoposide has marked schedule dependence, With toxic effects in the G2
phase.
It causes protein-linked DNA strand breaks by inhibiting topoisomerase II
Although Etoposide does not bind directly to the DNA. it stabilizes
covalent intermediate form of the DNA—topoisontcrasce II complex
Med Uses
Etoposide in combination with other chemotherapeutic agents is the first
choice treatment for small cell lung cancer
61. It also ineffective in combination with other
agents in refractory testicular tumors
it has been used alone or in combination
against acute non-lymphocytic leukemias.
Hodgkin's disease. non-Hodgkin's lymphornas,
and Kaposis sarcoma.
TOXICITY
1.hypersensitivity.
2 Dose-limiting bone marrow depression is the
most significant toxicity