CCC100:

ICI CHEMOTHERAPY & ANTICANCER AGENTS’

ADMINISTRATION COMPETENCY COURSE
10/08/2020

ANTINEOPLASTICS
DR WATA DAVID
KNH
ONCOLOGY PHARMACIST
Email: [email protected]

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 CLASSIFICATION

• Alkylating agents
• Antimetabolites.
• Antitumor antibiotics
• Drugs from plant origin
• Miscellaneous agents

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 ALKYLATING AGENTS
Nitrogen mustards Mechlorethamine, Cyclophosphamide, ifosfamide,
melphalan, chlorambucil, bendamustine

Alkyl sulphonates Busulphan

Ethylene imines Thiotepa

Methylhydrazine Procarbazine

Triazenes Dacarbazine, temozolomide

Nitrosoureas Carmustine, lomustine, streptozocin

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 ALKYLATING AGENTS

• The chemotherapeutic alkylating agents have in

common the property of forming highly reactive
carbonium ion intermediates.
• These reactive intermediates covalently link to
sites of high electron density, such as phosphates,
amines, sulfhydryl, and hydroxyl groups.
• They interfere with DNA integrity and function
and to induce cell death in rapidly proliferating
tissues.
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 ALKYLATING AGENTS

• Any of these effects can contribute to both the

mutagenic and the cytotoxic effects of
alkylating agents.
• The extreme cytotoxicity of the bifunctional
alkylators correlates closely with interstrand
cross-linkage of DNA.

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 CYCLOPHOSPHAMIDE
• Cyclophosphamide is activated (hydroxylated) by CYP2B6,
with subsequent transport of the activated intermediate
to sites of action.
• The selectivity of cyclophosphamide against certain
malignant tissues may result in part from the capacity of
normal tissues to degrade the activated intermediates via
aldehyde dehydrogenase, glutathione transferase, and
other pathways.
• Indicated in ALL, NHL, HL, CLL, BC, STS, GTD, mycosis
fungoides, neuroblastoma, ovarian ca, also: nephrotic
syndrome, vasculities
 CYCLOPHOSPHAMIDE
• BM suppression.
• Hemorrhagic cystitis, pyelitis, ureterities, & hematuria.
• Cardiotoxicity esp in high doses. CHF, arrythmias, heart
block, pericardities, myocardities.
• Pulmonary toxicity: pneumonities, pulmonary fibrosis,
pulmonary VOD.
• Nausea and vomiting.
• Alopecia
• Reproductive toxicity: amenorrhea, azoospermia, gonadol
suppression, impaired oogenesis
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 IFOSFAMIDE
• Ifosfamide is an analogue of cyclophosphamide.
• Indicated in germ cell tumors, STS, testicular Ca,
osteosarcoma.
• Requires mesna + hydration (2L) each day
• Ifosfamide has a similar toxicity profile as
cyclophosphamide.
• it causes greater platelet suppression,
neurotoxicity, nephrotoxicity, and urothelial
damage
 ADVERSE EFFECTS

• severe neurological toxicity, including

hallucinations, coma, and death, with
symptoms appearing 12 h to 7 days after
beginning the ifosfamide infusion.
• This toxicity may result from a metabolite,
chloroacetaldehyde.
• Ifosfamide also causes nausea, vomiting,
anorexia, leukopenia, nephrotoxicity, and VOD
of the liver.
 MELPHALAN

• Indicated in myeloma, BM transplant,

retinoblastoma.
• Non vesicant.
• Milder side effect profile. Nausea, vomiting,
alopecia.
• Oral & IV administration.
 CHLORAMBUCIL

• Indicated in CLL & HL.

• Oral administration
• Marked hypoplasia of the bone marrow may be
induced with excessive doses, but the
myelosuppressive effects are moderate, gradual,
and rapidly reversible.
• GI discomfort, azoospermia, amenorrhea,
pulmonary fibrosis, seizures, dermatitis, and
hepatotoxicity rarely may be encountered.
 DACARBAZINE

• Dacarbazine functions as a methylating agent

after metabolic activation to the monomethyl
triazeno metabolite MTIC.
• Used for HL, malignant melanoma, soft tissue
sarcomas.
• A/E: alopecia, N/V, anorexia, BM suppression,
local pain on infusion (irritant).
 TEMOZOLOMIDE

• Indicated in gliomas, astrocytoma, CTCL, STS,

NETS,
• Temozolomide, like dacarbazine, forms the
methylating metabolite MTIC.
• Oral & IV administration.
• A/E incl: peripheral edema, fatigue, headache,
convulsions, hemiparesis, alopecia, skin rash,
NVD, lymphocytopenia, thrombocytopenia,
leucopenia, weakness, fever
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 PROCARBAZINE
• Indicated in malignant brain tumors HL.
• The drug is a weak MAO inhibitor;
• Procarbazine has disulfiram-like actions.
• The drug is highly carcinogenic, mutagenic, and
teratogenic and is associated with a 5%–10% risk of
acute leukemia in patients treated with MOPP.
• A/E: edema, flushing, apprehension, ataxia, fever, chills,
confusion, depression, alopecia, dermatities, NVD,
↓fertility in males, 2nd cancers, BM suppression,
eosinophilia, HSR, hearing loss.
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 NITROSOUREAS: LOMUSTINE

• Indicated in 1O & 2O brain tumors, HL,

• nitrosoureas, exert their cytotoxicity through
the spontaneous breakdown to an alkylating
intermediate, the 2-chloroethyl diazonium ion.
• A/E: NV, BM suppression, acute leukemia, ↑
liver enzymes, alopecia, azotemia, blindness,
BM dysplasia etc

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 ETHYLENEIMINES
• Thiotepa In standard doses produces little toxicity other
than myelosuppression & mucositis; it is used for high-
dose chemotherapy regimens in transplants for
hematological malignancies, in which it causes both
mucosal and CNS toxicity.
• Altretamine is chemically similar to
(triethylenemelamine)TEM and has been used to treat
ovarian cancer.
• A/Es incl: myelosuppression and neurotoxicity,
peripheral and central neurotoxicity (ataxia, depression,
confusion, drowsiness, hallucinations, dizziness, and
vertigo), nausea & vomiting, renal dysfunction, rash
 ANTIMETABOLITES

• Folate analogues [methotrexate, pemetrexed]

• Purine analogues [6MP, 6TG, fludarabine]
• Pyrimidine analogues [5FU, capecitabine,
tegafur, cytarabine, gemcitabine]
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 METHOTREXATE
• Methotrexate: used in management of paediatric A.L.L,
choriocarcinoma, NHL, breast ca, ovarian ca, head & neck
ca., osteogenic sarcoma. also indicated in autoimmune
disease & rheumatological conditions.
• Adverse effects: myelosuppression, GI epithelial injury, oral
mucositis, renal impairment, alopecia, dermatitis, allergic
interstitial pneumonitis, nephrotoxicity (after high-dose
therapy), defective oogenesis or spermatogenesis, abortion
and teratogenesis.
• Oral and IV formulations.
• Can be administered orally, IV, IM & IT.
 HDMTX
• The administration of HDMTX has the potential for renal
toxicity, related to the precipitation of the drug, a weak
acid, in the acidic tubular fluid.
• Dose = 1g/m2
• vigorous hydration and alkalinization of urine pH is
required prior to drug administration.
• Leucovorin should be administered 24 hours after the
methotrexate infusion administration to prevent A/E of
methotrexate e.g. mucosities.
• Doses > 1g/m2 should be done in hospitals with specialists
experienced in administration of HDMTX.
 PEMETREXED
• It is avidly transported into cells via the reduced
folate carrier and is converted to PGs that inhibit
TS and glycine amide ribonucleotide
transformylase, as well as DHFR.
• It has activity against ovarian cancer,
mesothelioma, and adenocarcinomas of the lung.
• Note: requires daily folate & 3 weekly Vit B12 IM
(refer to regimen for precise scheduling & dose).
• A/E: Fatigue, rash, nausea, skin desquamation,
stomatities, diarrhea, BM suppression, pharyngities
 5FU
Mercaptopurine Fludarabine

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 PYRIMIDINE ANALOGUES

• Inhibit RNA and DNA function.

• inhibit the synthesis of essential precursors of
DNA.
• Others, such as the cytidine and adenosine
nucleoside analogues, become incorporated
into DNA and block its further elongation and
function
 5FU
• Used in management of colon &rectal cancers, anal ca,
pancreatic ca, gastric ca, head & neck cancers, ca breast.
• Is incorporated into RNA & also inhibits TS.
• A/Es: confusion, disorientation, headache,
• Alopecia, dermatitis, nail changes, hand& foot
syndrome, pruritis, rash, photosensitivity.
• Anorexia, diarrhea, nausea & vomiting, stomatitis,
mucositis, ulceration.
• BM suppression, photophobia.
 CAPECITABINE

• Oral pro-drug of 5FU.

• Used in metastatic ca breast, colon & rectal cancer,
gastric cancer etc.
• Adverse effects: anorexia and nausea, followed by
stomatitis and diarrhea.
• Mucosal ulcerations occur throughout the GI tract and
may lead to fulminant diarrhea, shock, and death,
particularly in patients who are DPD deficient.
• Hand and foot syndrome, coronary artery vasospasms
 CYTARABINE
• Ara-CTP competes with dCTP for incorporation into DNA by DNA
polymerases → inhibition of DNA polymerase & blockade of DNA
elongation
• Ara-C is indicated for induction and maintenance of remission in AML .
• used treatment of patients with other leukemias, such as ALL, CML in the
blast phase, APL, and high-grade lymphomas.
• A/Es include GI disturbances, stomatitis, conjunctivitis, reversible hepatic
enzyme elevations, noncardiogenic pulmonary edema and dermatitis,
dyspnea, fever, and pulmonary infiltrates in high dose therapy.
• myelosuppression.,
• Cerebellar toxicity, manifesting as ataxia and slurred speech, and cerebral
toxicity (seizures, dementia, and coma) in IT therapy
• IV & IT administration.
 GEMCITABINE
• Gemcitabine, a difluoro analogue of deoxycytidine,
• Indicated in metastatic pancreatic; non-squamous,non–
small cell lung; ovarian; and bladder cancer, breast ca.
• A/Es: hemolytic uremic syndrome (monitor renal function.
• Hepatotoxic (hepatic failure)
• Capillary leak syndrome.
• Interstitial pneumonitis, pulmonary edema & pulmonary
fibrosis.
• Drowsiness, skin rash, alopecia, proteinuria, hematuria,
BM suppression.
 MERCAPTOPURINE
• Indicated in ALL.
• Inhibits formation of adenine and guanine nucleotides
intracellulary after conversion to the triphosphate
form.
• A/Es – mainly myelosuppression. Dose adjusted
according WBC counts.
• Anorexia, nausea, & vomiting.
• Jaundice and hepatic enzyme elevations occur in up to
one-third of adult patients treated with 6MP and
usually resolve on discontinuation of therapy.
 NATURAL PRODUCTS
• Vinca alkaloids [vincristine, vinblastine, vinorelbine ]
• Epipodophyllotoxins [etoposide, teniposide]
• Camptothecins [irinotecan, topotecan]
• Taxanes [docetaxel, paclitaxel, ]
bind specifically to β-tubulin and to block its polymerization with α-tubulin
into microtubules. The mitotic spindle cannot form and cell division arrests
in metaphase.
 VINCA ALKALOIDS

• Vincristine is indicated in ALL, lymphomas, STS,

paediatric solid tumors, LCH.
• A/E: edema, myocardial ischemia,
Hyperuricaemia, SIADH, Bladder atony, dysuria,
polyurea, urinary retention, loss of deep tendon
reflexes, paraesthesia, peripheral neuropathy,
sensorimotor dysfunction.
• Vinblastine indicated in HL, KS, LCH, Ca bladder.
• Vinorelbine indicated in BC, NSCLC.
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 TAXANES

• Docetaxel indicated in BC, H&N Ca, NSCLC, Ca

prostate, gastric Ca.
• A/E: BM suppression, neuropathy, alopecia, fluid
retention, NV, HSR, weakness.
• Paclitaxel indicated in BC, NSCLC, KS, bladder Ca,
cervical Ca, Ca ovary.
• A/E: flushing, edema, ECG changes, NVD,
mucosities, BM suppression, ↑ liver enzymes,
peripheral neuropathy, arthralgia, myalgia, HSR
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 CAMPTOTHECINS
• Inhibitors of he topoisomerase 1 enzyme thus
preventing religation of cleaved DNA strands
leading to double strand DNA breaks.
• Irinotecan indicated in colorectal cancer,
pancreatic ca, recurrent glioblastoma, STS.
• A/E: vasodilation, rhinitis, lacrimation, salivation ,
fever, dehydration, diarrhea, abd pain, cramps,
mucosities, BM suppression.
• Topotecan indicated in 2nd line for cervical ca,
SCLC, retinoblastoma.
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 EPIPODOPHYLOTOXINS
• Topoisomerase 2 inhibitor+ inhibits
mitochondrial transport.
• Etoposide Indicated in SCLC, germ cell tumors,
thymoma, AML, lymphomas, GTD,
neuroblastoma, retinoblastoma.
• A/E: alopecia, NVD, BM suppression,
hypotesnion, stomatities, anaphylactoid reaction.
• Teniposide indicated in 2nd line management of
ALL.

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 ANTI CANCER ANTIBIOTICS

• Anthracyclines & anthrecendiones

• Actinomycins
• Bleomycins

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 ANTHRACYCLINES
• Intercalate DNA thus inhibit DNA transcription
& translation.
• Topoisomerase 2 inhibitor.
• Doxorubicin, daunorubicin, epirubicin.
• Doxorubicin indicated in BC, acute leukemias,
lymhomas, neuroblastoma, wilms, STS,
osteosarcoma.
• Daunorubicin indicated in acute leukemias.
• Epirubicin indicated in BC, gastric ca
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 ANTHRACYCLINES

• A/Es: CVS- acute: AV block, bradycardia, ECG

abnormalities, extra systoles, tachyarrythmia.
• Delayed: ↓LVEF, CHF(cardiomegaly, ascites,
edema, gallop rhythm, pleural effusion,
tachycardia) myocarditis, pericarditis.
• malaise, alopecia, itching, radiation recall,
discoloration of body fluids, flare at injection site,
urticaria.
• BM suppression, N/V,
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 BLEOMYCIN

• Commercial preparation: bleomycin A1&A2

• Causes DNA strand breaks.
• Indicated in HL, germ cell tumors, KS.
• A/Es are cutaneous toxicities, including
hyperpigmentation hyperkeratosis, erythema,
even ulceration, retroperitoneal & pulmonary
fibrosis.

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 ACTINOMYCIN D
• Intercalates DNA preventing DNA transcription +
inhibits DNA polymerase.
• Indicated in rhabdomyosarcoma, wilms tumor &
GTD.
• A/Es incl: anorexia, nausea, and vomiting,
Proctitis, diarrhea, glossitis, cheilitis, and
ulcerations of the oral mucosa, BM suppression.

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 MISCELLANEOUS

• Platinums
• Steroids
• Retinoids
• Enzymes
• Others

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 PLATINUMS
• Aquated ligands covalently bind to nucleophilic
sites on DNA similar to the alkylators.
• Cisplatin indicated in osteosarcoma, SCLC, NSCLC,
H&N ca, esophageal, gastric ca, germ cell tumors,
cervical ca, endometrial ca, ovarian ca. bladder ca
• Carboplatin indicated in NSCLC, H&N ca, germ cell
tumors, cervical ca, endometrial ca, ovarian ca.
bladder ca, BC, STS.
• Oxaliplatin indicated in colorectal ca, pancreatic ca,

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 PLATINUMS
• Cisplatin A/E: ↓Ca ↓PO3 ↓Mg, ↓K.
Myelosuppression, NV, ↑AST&ALT, ototoxicity,
neuropathies.
• Carboplatin A/E: BM suppression, HSRs, NV, pain,
↓Na, ↓Mg, ↓ Ca & ↓K. ↑ in ALT & AST,
Weakness, ↓ creatinine clearance, peripheral
neuropathy.
• Oxaliplatin A/E: peripheral neuropathies, HSR, BM
suppression, NVD, ↑AST&ALT, skin rash, alopecia

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 OTHERS

• L-asparaginase: indicated in ALL.

• ATRA: indicated in AML M3
• Isotretinoin: indicated in neuroblastoma
• Mitomycin: indicated in anal ca
• Prednisolone: indicated in ALL, lymphomas, ca
prostate.
• As2O3: indicated in AML.
• Hydroxyurea: indicated in SCD, CML,
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 REFERENCES

• *Ralhan, Ranju & Kaur, Jatinder. (2007). Alkylating agents and cancer therapy. Expert Opin Ther Pat. 17. 1061-1075.
10.1517/13543776.17.9.1061.
• *oncology nursing society/ continous professional development programs
• * Lexicomp drug information handbook for oncology 14 th edition. American Pharmacists Association
• * Goodman and Gilmans Pharmacological Basis of Therapeutics 13 th Edition. McGraw Hill. Laurence Brunton

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