CYTOTOXIC DRUGS

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 CYTOTOXIC DRUG
• (sometimes known as antineoplastics) describe a group of medicines that contain chemicals
which are toxic to cells, preventing their replication or growth, and so are used to treat cancer.

• Combination therapy – the use of two or more chemotherapy agents to treat cancer – was
adopted and led to improved response rates and increased survival times.

• Chemotherapy is used as the only treatment of cancer, or it may used in conjunction with other
modalities such as radiation, surgery, and biologic response modifiers (BRMs).
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 ALKYLATING
DRUGS
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 Alkylating Drugs
● One of the largest groups of anticancer drugs.
● It damage the cell’s DNA by cross-linkage of DNA strands,
abnormal base pairing, or DNA strand breaks, thus preventing the
reproduction of cancer cells.
● They are used to treat many different types of cancer including
leukemia, lymphoma, multiple myeloma, sarcoma, and solid
tumors such as those of the breast, ovary, uterus, lung, bladder, and
stomach.
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 5 CLASSES
OF
ALKYLATING
DRUGS
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 5 classes of Alkylating Drugs
1 2 3
Nitrogen Alkyl
Nitrosoureas
Mustards Sulfonates

4 5

Triazines Ethylenimines
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 General Adverse Reactions
Adverse Reactions

Bone Marrow Suppression/ Myelosuppression

Low RBC count (anemia)
Low WBC count (leukopenia)
Low platelet count (thrombocytopenia)

Gastrointestinal Disturbances
Anorexia
Nausea and vomiting
Diarrhea
Mucositis (stomatitis)

Other
Alopecia
Fatigue
infertility
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 NITROGEN MUSTARDS

01
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 Nitrogen Mustards
● it is not found naturally in the environment
● HN-1 originally was designed to remove warts but
later on, it was identified as a potential chemical
warfare agent.
● HN-2 was designed for military agent but was later
used in cancer treatment.
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 MECHLORETHAMINE
The first clinically used nitrogen mustard and is the
most reactive of the drugs in this class. It is used
topically for treatment of CTCL as a solution that is
rapidly mixed and applied to affected areas. It has been
largely replaced by cyclophosphamide, melphalan, and
other more stable alkylating agents.
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 MECHLORETAMINE
ROUTE AND DOSAGE USES AND CONSIDERATIONS

HODGKIN DISEASE:
A: IV: 0.2 mg/kg or 6 mg/m2 as single dose FOR HODGKIN DISEASE, LEUKEMIAS, SOLID
TUMORS AND EFFUSION CAUSED BY
CANCER. This drug is contraindicated in patients
CLL:
with active infections
A: IV: 6 mg/m2 q4wk
• PB: 94% - 96 %
CML: • t½: 40 min
A: IV: 0.4 mg/kg or 6 mg/m2 monthly
Other dosing regimen and routes are available
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 CYCLOPHOSPHAMINE
• An analogue of nitrogen mustard and has activity against many
neoplastic diseases such as Hodgkin and non-Hodgkin
lymphoma (NHL), acute and chronic lymphocytic leukemia
(CLL) and etc.

• Used for immunologic disorders such as lupus nephritis, and

has been shown to prevent progressive renal scarring, preserve
renal function, induce renal remission and decrease end-stage
renal failure.
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 CYCLOPHOSPHAMIDE (Cont.)
• This drug is a severe vesicant, that causes tissue necrosis if it infiltrates into the
tissues.

• Given orally or intravenously

• A prodrug that is activated and extensively metabolized by the liver.

• 5% or 25% of the drug is eliminated by the kidney as unchanged, and its

elimination half life is 3-12 hours.

• Patients should report all medications they are taking, including over-the-counter
(OTC) medicines and herbal supplements.

• Patient should be hydrated while taking the drug to prevent hemorrhagic cystitis
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 Sodium 2- mercaptoethanesulfonate

A chemoprotectant drug often given with

high-dose cyclophosphamide to inactivate
urotoxic metabolites to reduce the incidence
of hemorrhagic cystitis.
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 CHLORAMBUCIL
• almost exclusively used in treating CLL
• The cytotoxic effects of chlorambucil on the bone marrow,
lymphoid organs, and epithelial tissues are similar to those
observed with other nitrogen mustards. As an orally
administered agent, chlorambucil is well tolerated in small
daily doses and provides flexible titration of blood counts.
Nausea and vomiting may result from single oral doses of 20
mg or greater.
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 CHLORAMBUCIL
ROUTE AND DOSAGE USES AND CONSIDERATIONS

FOR CLL AND NHL:

Palliative CLL, Hodgkin Disease, and NHL: • Monitor for bone marrow suppression or
A: PO: 0.1-0.2 mg/kg/d (4-10 mg/d) for 3-6 pancytopenia
weeks • PB: 99 %
• t½: 1.5 h
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 IFOSFAMIDE
● Ifosfamide is an analogue of cyclophosphamide.
● Ifosfamide is approved for treatment of patients with relapsed
germ cell testicular cancer and is frequently used for first-
time treatment of pediatric or adult patients with sarcomas
● It is a common component of high dose chemotherapy
regimens with bone marrow or stem cell rescue
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 IFOSFAMIDE
ROUTE AND DOSAGE USES AND CONSIDERATIONS

A: IV: 1.2-2g/m2/d for 5 d in combination with FOR TESTICULAR CANCER:

MESNA; repeat every 3 wk after recovery from • Monitor for hemorrhagic cystitis
hematologic toxicity. Mesna is usually given • PB: negligible
concomitantly to prevent hemorrhagic cystitis • t½: 7-15 h
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 BENDAMUSTINE
● approved for treatment of CLL and non-Hodgkin
lymphoma.
● rapidly degraded through sulfhydryl interaction and adduct
formation with macromolecules; less than 5% of the parent
drug is excreted in the urine intact
● The parent drug has a plasma t 1/2 of about 30 min.
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 BENDAMUSTINE
ROUTE AND DOSAGE USES AND CONSIDERATIONS

CLL:
A: IV: 100 mg/m2 on days 1 and 2, repeated q28d FOR CLL AND NHL:
for up to 6 cycles • Monitor for bone marrow depression
• Assess for tumor lysis syndrome and skin
reactions
NHL: • PB: 94% - 96 %
A: IV: 120 mg/m2 on days 1 and 2, repeated • t½: 40 min
q21d for up to 8 cycles
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 MELPHALAN
● used to treat multiple myeloma and, less commonly, in high-dose
chemotherapy with bone marrow transplantation. The general
pharmacological and cytotoxic actions of melphalan are similar
to those of other bifunctional alkylators. The drug is not a
vesicant.
● may be used in myeloablative regimens followed by bone
marrow or peripheral blood stem cell reconstitution
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 MELPHALAN
ROUTE AND DOSAGE USES AND CONSIDERATIONS

MULTIPLE MYELOMA:
A: PO: 6 mg daily for 2-3 wks; maint; 2 mg/d;
adjust 1-3 mg/d based on hematologic response FOR MULTIPLE MYELOMA AND OVARIAN
A: IV: 16 mg/m2 q2wk for 8 doses; maint; 16 CANCER:
mg/m2 q4wk • Do not confuse with alkeran with Leukeran or
Myleran
OVARIAN CANCER: • PB: 20% -30 %
A: PO: 200 mcg/kg/d for 5 d; repeat q4-5wk • t½: 1.25- 1.5 h
based on hematologic response
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 ESTRAMUSTINE
ROUTE AND DOSAGE USES AND CONSIDERATIONS

FOR PALLIATIVE TREATMENT OF PROSTATE

CANCER.
A: PO: 14 mg/kg/d or 600 mg /m2/d in 3-4
• Gynecomastia and impotence may occur
divided doses
• PB: UK
• t½: 20-24 h
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 NITROSOUREAS
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 Nitrosoureas
● Have an important role in the treatment of brain tumors and find
occasional use in treating lymphomas and in high-dose regimens
with bone marrow reconstitution. They function as bifunctional
alkylating agents but differ from conventional nitrogen mustards in
both pharmacological and toxicological properties.
● Cross-blood barrier, making them useful in the treatment of brain
cancer.
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 CARMUSTINE (BCNU)
● its ability to cross the blood-brain barrier, an important
property in the treatment of brain tumors.
● used in the treatment of malignant gliomas. An
implantable carmustine wafer is available for use as an
adjunct to surgery for recurrent glioblastoma multiforme
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 CARMUSTINE (BCNU)
ROUTE AND DOSAGE USES AND CONSIDERATIONS

FOR HODGKIN DISEASE, NHL, MULTIPLE

MYELOMA, AND BRAIN TUMORS.
A: IV: 150-200 mg/m2 single dose q6wk or 75-
• Monitor for bone marrow suppression and
100 mg/m2/d for 2 days q6wk
pulmonary symptoms
• PB: UK
• t½: 5-30 mins
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 STREPTOZOCIN
● used in the treatment of human pancreatic islet cell
carcinoma and carcinoid tumors.
● has a methylnitrosourea moiety attached to the 2-
carbon of glucose. It has a high affinity for cells of
the islets of Langerhans and causes diabetes in
experimental animals.
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 STREPTOZOCIN
ROUTE AND DOSAGE USES AND CONSIDERATIONS

FOR PANCREATIC CANCER.

A: IV: 500 mg/m2/d for 5 d q4-6 wk;
• Do not confuse with streptomycin
doses above 500 mg/m2 are not recommended
• PB: UK
• t½:30-45 mins
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 LOMUSTINE (CCNU)
ROUTE AND DOSAGE USES AND CONSIDERATIONS

FOR HODGKIN DISEASE AND MALIGNANT

GLIOMA.
FOR HODGKIN DISEASE AND MALIGNANT
GLIOMA:
• Monitor for bone marrow suppression and
liver function
A:PO: 100-130 mg/m2 q6wk
• PB: UK
• t½: 16 h – 2 d
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 ALKYL SULFONATES
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 BUSULFAN
● the initial oral dose of busulfan varies with the total
leukocyte count and the severity of the disease
● primarily used in high-dose regimens, in which
pulmonary fibrosis, GI mucosal damage, and hepatic
VOD are important toxicities.
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 BUSULFAN
ROUTE AND DOSAGE USES AND CONSIDERATIONS

FOR MYELOCYTIC CANCER

• Monitor for seizures and cerebral

A: PO: 4-8 mg/d hemorrhage
• PB: 32%
• t½: 2.5 h
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TRIAZINES
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 DACARBAZINE (DTIC)
● a methylating agent after metabolic activation to the monomethyl
triazeno metabolite MTIC. It kills cells in all phases of the cell
cycle. Resistance has been ascribed to the removal of methyl
groups from the O6-guanine bases in DNA by MGMT.
● The primary clinical indication for dacarbazine is in the
chemotherapy of Hodgkin disease
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 DACARBAZINE (DTIC)
ROUTE AND DOSAGE USES AND CONSIDERATIONS

MELANOMA:
A: IV: 250 mg/m2/d for 5 d; repeat q3wk for 2 FOR HODGKIN DISEASE AND MALIGNANT
more cycles MELANOMA:

• Monitor hepatic function

• PB: minimal
HODGKIN DISEASE:
• t½: 5 h
A: IV: 375 mg/m2 on day 1 q2wk for 12 cycles
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 ETHYLENIMINES
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 ALTRETAMINE
● Its precise mechanism of cytotoxicity is unknown,
although it can alkylate DNA and proteins.
● It is a palliative treatment of patients with persistent or
recurrent ovarian cancer following cisplatin-based
combination therapy
● The drug undergoes rapid demethylation in the liver
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 ALTRETAMINE
ROUTE AND DOSAGE USES AND CONSIDERATIONS

A: PO: 260 mg/m2/d on 4 divided doses after FOR OVARIAN CANCER:

meals and at bedtime for 14-21 d in 28-d
cycles; • PB: weakly
Drug holiday for > 14 d then restart at 200 • t½: 4.7-10.2 h
mg/m2/d
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 PLATINUM
COORDINATION
COMPLEXES
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 PLATINUM COORDINATION COMPLEXES
• Platinum coordination complexes have broad antineoplastic
activity and have become the foundation for treatment of
ovarian, head and neck, bladder, esophagus, lung, and colon
cancers
• Although cisplatin and other platinum complexes do not form
carbonium ion intermediates like other alkylating agents or
formally alkylate DNA, they covalently bind to nucleophilic
sites on DNA and share many pharmacological attributes with
alkylators
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 CISPLATIN
Cisplatin is used to treat various types of
cancer. It is a chemotherapy drug that
contains platinum. It is used to slow or stop
cancer cell growth.
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 CISPLATIN (cont.)
• Cisplatin, in combination with bleomycin, etoposide, or with
ifosfamide and vinblastine, cures 90% of patients with testicular
cancer. Used with paclitaxel, cisplatin or carboplatin induces complete
response in the majority of patients with carcinoma of the ovary.
Cisplatin produces responses in cancers of the bladder, head and
neck, cervix, and endometrium; all forms of carcinoma of the lung;
anal and rectal carcinomas; and neoplasms of childhood.

• The drug also sensitizes cells to radiation therapy and enhances

control of locally advanced lung, esophageal, and head and neck
tumors when given with irradiation.
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 CISPLATIN
ROUTE AND DOSAGE USES AND CONSIDERATION

BLADDER CANCER
A: IV: 50-70 mg/m2 q3-4wk FOR BLADDER, OVARIAN AND NSCLC.

• Monitor for CNS function

OVARIAN CANCER • Reversible posterior leukoencephalopathy may
A: IV: 50-75 mg/m2 q21d occur
• PB: 90 %
TESTICULAR CANCER • t½: 30-100 h, dose related
A: IV: 20 mg/m2 for 5d; repeat q3wk for 2
more cycles
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 CARBOPLATIN
carboplatin is much less reactive than cisplatin, the
majority of drug in plasma remains in its parent
form, unbound to proteins. Most drug is eliminated
via renal excretion
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 CARBOPLATIN (cont.)
• Carboplatin and cisplatin are equally effective in the treatment of patients with
suboptimally debulked ovarian cancer, non–small cell lung cancer, and extensive-
stage small cell lung cancer; however, carboplatin may be less effective than
cisplatin in the treatment of patients with germ cell, head and neck, and esophageal
cancers.

• Carboplatin is an effective alternative for responsive tumors in patients unable to

tolerate cisplatin because of impaired renal function, refractory nausea, significant
hearing impairment, or neuropathy, but doses must be adjusted for renal function.

• may be used in high-dose therapy with bone marrow or peripheral stem cell rescue
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 CARBOPLATIN
ROUTE AND DOSAGE USES AND CONSIDERATION

NEW CANCER
A: IV: 300 mg/m2 in combination with FOR ADVANCED OVARIAN CANCER.
cyclophosphamide q4wk for 6 cycles
• Usually given as combination therapy
• PB: UK
• t½: 1.5-2.5 H
RECURRENT CANCER
A: IV: 360 mg/m2 q4wk
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 OXALIPLATIN
● has a short t½ in plasma, probably as a result of its rapid
uptake by tissues and its reactivity
● exhibits a range of antitumor activity (colorectal and
gastric cancer) that differs from other platinum agents.
● Oxaliplatin’s effectiveness in colorectal cancer is perhaps
due to its MMR- and HMG-independent effects.
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 OXALIPLATIN
ROUTE AND DOSAGE USES AND CONSIDERATION

FOR METASTIC COLORECTAL CANCER.

• Used with 5-FU (fluorouracil) and leucovorin

A: IV: 85 mg/m2 on day 1 q2wk for 12 cycles (FOLFOX4)
• Assess for pulmonary complication
• PB: >90%
• t½: 391 h
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 THANK YOU
for
Listening!
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