Antimalignants

1) Antimetabolites
2) Alkylating agents
3) Cytotoxic antibiotics
4) Natural Products
a. Vinca alkaloids
b. Epidophyllotoxins
c. Camptothecin
d. Taxanes
5) Hormones and Antihormones
a. Estorgens
b. Antiestrogens
c. Androgens
d. Antiadnrogens
e. Progestins
f. Gonadotropin releasing hormone
g. Adrenocorticoids
6) Immunosuppressents
7) Miscellaneous
a. Enzymes
b. Biological response modifiers
c. Platinum coordination complexes
d. Substituted urea
e. Aromatase inhibitor (breast cancer)

1) Antimetabolites
Methotrexate
MOA
Blocks the enzyme dihydrofolate reductase (DHFR) in the synthesis of purines and
pyrimidines and therefore inhibit cell replication. DHFR is responsible for the reduction
of folate to tetrahydrofolate which is a 1 carbon carrier.
- CCS – works in the S phase of cell cycle
Indications
- Treatment of malignancies (specifically for dividing cells)

Contraindications/Adverse Effects
- Potentially Nephrotic at high doses
- May be toxic if Pt had ascites due to storage of drug
- Myelosuppression – neutropenia, thrombocytopenia, mucositis, diarrhea
- Pulmonary and hepato- toxicities if given long term

Note
- causes a build-up of TOXIC intermediate FH2 polyglutamate.
 - Calcium Leucovorin is an antidote to drug. Host cells are rescued while
cancer cells are less effected by the antidote. (due to level of polyglutamation
of Methotrexate in the cells)
- Filgrastim (Granulocyte growth factor G-CSF) has shortened periods of
leucopenia after high doses of chemotherapy

5-Fluorouracil, (Floxuridine)
MOA
Inhibition of the enzyme thymidylate synthase preventing cells from incorpating
thymine into their DNA. Therefore they suffer a “THYMINE-LESS DEATH”

Indications
- Metastatic carcinoma of the breast
- Carcinoma of GI
- Hepatoma
- Carcinoma of ovary, bladder, prostate, pancrease, oropharynx
- Metastatic carcinoma of the colon (Floxuridine)

Contraindications/Adverse Effects
- Anorexia and nausea
- Stomatitis and diarrhea
- Myelosuppression (bolus doses)
- Alopecia (hair loss)
- Effects tumor cells and normal cells equally

Cytarabine (cytosine arabinoside)

MOA
Cytarabine (araC) is incorporated into cellular DNA and prevents elongation of DNA
strand as well as interfering with template function.
(ONLY DNA synthesis is inhibited, not RNA or protein synthesis)

Indications
- Acute myelocytic leukemia (AML)

Azathioprine
Mercaptopurine
Fludarabine
MOA (CCS)
1) Prevents clonal expansion of B and T lymphocytes by conversion to nucleotide
6-thioinosinic acid causing inhibition of purine nucleotide interconversions

2) Prevents de novo purine synthesis by inhibiting PRPP Synthetase and PRPP

amidotransferase enzymes while drug is in nucleotide format. Blocking purine synthesis

3) Inhibits DNA formation by false substrate action (salvage pathway)

Indications
- PREVENT graft rejections by lowering immune response
 - Treatment of autoimmune diseases (Crohn’s, RA)
- Treatment of delayed hypersensitivity reactions
- Treatment of various malignancies

Contraindications
- individuals who are already immuno-compromised
Notes
- highly inactivated by liver, therefore IV dosage
- causes bone marrow suppression
- drug interactions with allopurinol causes toxic levels of mercaptopurine
(intermediate) due to competition for enzyme  allopurinol preferentially binds
to enzyme

Pentostatin
MOA
Blocks the enzyme adenosine deaminase (ADA) which is essential in two steps of DNA
synthesis. (adenosineinosine and deoxyadenosinedeoxyinosine)

Indications
- Treatment of Hairy Cell Leukemia

2) Alkylating Agents
Cyclophosphamide (Ifosphamide)
MOA (CCNS)
Become strong electrophiles through the formation of cabonium intermediates which
bond with nucleophiles, like the N7 of guanine, and causes abnormal base-pairings and
breakage. Pro-drug converted in the liver to a active nitrogen mustard which, together
with acrolein are end products of metabolism

Indications
- Chronic lymphatic leukemia
- SOLID tumors
- Non-Hodgkin’s lymphoma
- Ovarian carcinoma
- Neuroblastoma
- Immunosuppressive

Contraindications/Adverse effects
- Active mustard is VERY nephrotoxic
- Acrolein causes chemical cystitis (hemorrhagic)
- Myelosuppressive with less severe thrombocytopenia
- Permanent amenorrhea and azoospermia
- Leukemogenic
- Renal and bladder toxicity
- GI toxicity due to denudation
- Pulmonary fibrosis

Note
- Give IV, Pro-drug that needs conversion
 - Give with HIGH WATER DOSES to prevent reabsorbtion in the nephron
- MESNA is antidote which conjugates toxic metabolites like acrolein in the urine
- Inappropriate secretion of ADH (not enough) will cause water-intoxication (give
demeclocycline to block effects of ADH)

Bulsulphan
MOA (CCNS)
Selective depression of granulocytopoesis.

Indications
- Treatment in Chronic Myelogenous Leukemia (CML)
- Treatment in Acute Myelogenous Leukemia (AML)

Contraindications/Adverse effects
- Busulphan lung – pulmonary fibrosis
- Busulphan tan – hyperpigmentation
- Adrenal suppression (can’t deal with stress)
- Thrombocytopenia

Carmustine
MOA
Enters brain and forms cross-linkages in the DNA chains causing abnormal base-pairing
and DNA breakage.

Indications
- Malignant astrocytomas and metastatic tumors of the brain

3) Cytotoxic Agents
Doxorubicin
MOA (CCNS, CCS)
Acts as a topoisomerase poison by integrating into the DNA and binding to the helical
groove preventing the topoisomerases from resealing helical breaks. Also causes free
radical formation which are damaging to the cells.

Indications
- Solid tumors of breast, endometrium, testes, lung
- ABVD in Hodgkin’s Disease
- CHOP in Hodgkin’s Lymphoma
- Sarcomas – osteogenic, Ewing’s, soft tissue
- Metastatic carcinoma of the thyroid

Contraindications/Adverse effects
- RESISTANCE may occur due to the active outward pumping of the drug
- Sever cardiomyopathy may occur
- Erythematous streaking at site of infusion
- Myelosuppression
- Alopecia
Note
- Must be given by FAST RUNNING IV to prevent extravasation
 - Dexrazoxane, an iron chelator, is the antidote that may prevent cardiac damage
- Dimethyl sulphoxide is antidote to prevent free radical ulceration
- Both mutagenic and carcinogenic
- Enhanced doxorubicin toxicity is seen with azathioprine

Daunorubicin
MOA (mainly CCNS)
Acts as a topoisomerase poison by integrating into the DNA and binding to the helical
groove preventing the topoisomerases from resealing helical breaks. Also causes free
radical formation which are damaging to the cells.

Indications
- Treatment of Leukemia

Contraindications/Adverse effects
- May cause red urine

Dactinomycin
MOA
Binds to DNA helix and prevents the transcription of the strand by RNA polymerase. It
may also cause single strand breaks in the DNA probably through free radical formation.

Indications
- Rhabdomyosarcoma
- Wilm’s rumor in children
- Ewing’s tumor
- Kapsoi’s sarcoma

Contraindications/Adverse effects
- hematopoietic suppression
- Pancytopenia – dose limiting property
- Proctitis, diarrhea, glossitis, cheilitis and ulcerations of oral mucosa
- Alopecia, anorexia, nausea, vomiting

Bleomycins
MOA
Causes fragmentation of DNA and cells accumulate in the G2 phase of the cell cycle
prevented from going forward. (mixture of two copper chelating peptides)

Indications
- Testicular caners
- Squamous carcinomas of the head, neck, lungs
- Lymphomas

Contraindications/Adverse effects
- VERY LITTLE myelosuppressions
 - Pulmonary toxicity (dry cough)
- Pulmonary Fibrosis
- Hyperthermia
- Skin blisters, pigmentation, hyperkeratosis

4) Natural Products
a. Vinca alkaloids
Vincristine
MOA (CCS)
Spindle poison. Bind to tubulin and prevent assembly of microtubules. (Act in M phase)

Indications
- Pediatric Leukemias
- Solid tumors (Hodgkin’s Disease)
- Rhabdomyosarcoma
- Lymphomas
- Neuroblastoma

Contraindications/Adverse effects
- Peripheral neuropathy
- Relatively bone marrow sparing

Note
- Christ my nerves!!!

Vinblastine
MOA (CCS)
Spindle poison. Bind to tubulin and prevent assembly of microtubules. (Act in M phase)

Indications
- Hodgkin’s (ABVD)
- Testicular carcinoma (VBC, VBE)

Contraindications/Adverse effects
- Myelosuppressive
- Leucopenia
- alopecia

Note
- Blast my bones!!!

b. Epidophyllotoxins
Etoposide
MOA
Stablilises the topoisomerase II-DNA complex causing double strand DNA breaks during
DNA replication. (S and G2 phases only)

Indications
- Testicular carcinoma
 - Diffuse lymphoma
- Hodgkin’s Disease
- Oat cell carcinoma of lung

Contraindications/Adverse effects
- Dose limiting leukemia
- Anaphylaxis
- Hepatic toxicity at high doses

c. Camptothecins
Topotecan
MOA
Topoisomerase 1 inhibitor causing single strand breaks in DNA.

Indications
- Colorectal, Ovarian, and small cell cancers

Contraindications/Adverse effects
- dose limiting neutropenia and thrombocytopenia

d. Taxanes
Paclitaxel
Docetaxel
MOA
Prohibit microtubule disassembly causing microtubular plates to accumulate and
dysfunctional spindles.

Indications
- Ovarian Cancer
- Breast Cancer

Contraindications/Adverse effects
- Hypersensitivity reactions
- Neutropenia
- Alopecia
- Cardiac arrhythmias (asymptomatic)
- Peripheral neuropathy (Paclitaxel)
- Damage to nails and fluid retention (Docetaxel)

Note
- Paclitaxel clearance is reduced with combined use of cisplatin causing toxicity.

5) Hormones and Antihormones

Tamoxifen (Antiestrogen)
MOA
Prevents estrogen from binding to estrogen receptors.

Indications
- Breast cancer treatment and prophylaxis
 - Infertility
- Gynecomastia
- Older women with inoperable tumors

Contraindications/Adverse effects
- Hot flashes
- Vaginal bleeding
- Hypercalcemia
- Peripheral edema

Flutamide (Antiandrogen)
MOA
Inhibits the translocation of steroid receptors to the nucleus. Non steroidal

Indications
- Prostatic cancers

Cyproterone (Antiandrogen)
MOA
Steroidal Androgen Receptor Agonist. Blocks receptors of testosterone on the prostate as
it blocks intracellular receptors for dihydrotestosterone.

Indications
- Prostatic cancers

Leuprolide (Gonadotrophin releasing hormone)

MOA
Acts as partial agonist at the GnRH receptors and may inhibit release of LH and FSH at
constant doses.

Indications
- Prostatic Carcinoma

Contraindications/Adverse effects
- Bone and back pain
- Gynecomastia
- Hematuria
- Impotence
- Testicular atrophy

6) Immunosuppressives (see Immunosuppressive Outline)

7) Miscellaneous
Asparaginase
MOA
Hydrolyses L-asparagine to ammonia and aspartic acid, thus depriving the cancer cell of
the amino acid asparagines for protein synthesis causing the cell to go through apoptosis.
Indications
- Acute lymphoblastic leukemia
Contraindications/Adverse effects
- Hypersensitivity reactions
- Toxic to CNS at high levels

Cisplatin
MOA
Diffuses into cell and chloride molecule is replaced by a water molecule activating drug.
Compound then reacts with DNA causing inhibition of replication and transcription by
DNA breaks and miscoding. Cell cycle phase differs with different cell types.

Indications
- Urinogenital cancers

Contraindications/Adverse effects
- Nephrotoxicity
- Electrolyte disturbances
- Nausea and vomiting

Note
- RAPID INJECTION and FLUSHING
- Vigorous hydration

Drug Combination Therapies

Breast Cancer CMF Cyclophosphamide
Methotrexate
5-Flurouracil

Pancreatic Cancer FAM 5-Flurouracil

Doxorubicin (Adriamycin)
Methortrexate

Ovarian Cancer CP Cyclophosphamide

CisPlatin

Testicular Cancer PVB CisPlatin

Vinblastine
Bleomycin

Non-Hodgkin’s Lymphoma CHOP Cyclophosphamide

Doxorubicin (Hydroxydaunorubicin)
Vincristine (Oncovorin)
Prednisone

Hodgkin’s Disease MOPP Mechlorethamine

Vincristine (Oncovorin)
Prednisone
Procarbazine
Hodgkin’s Disease ABVD Doxorubacin (Adrianmycin)
Bleomycin
 Vinblastine
Dacarbazine

1) Antimetabolites
Methotrexate
5-Flurouracil
(Floxuridine)
Cytarabine
Azathioprine
Mercaptopurine
Fludarabine
Pentostatin
2) Alkylating agents
Cyclophosphamide (Ifosphamide)
Bulsulphan
Carmustine
3) Cytotoxic antibiotics
Doxorubicin
Dactinomycin
Dactinomycin
Bleomycins
4) Natural Products
a. Vinca alkaloid
Vincristine
Vinblastine
b. Epidophyllotoxins
Etoposide
c. Camptothecin
Topotecan
d. Taxanes
Paclitaxel
Docetaxel
5) Hormones and Antihormones
a. Antiestrogens
Tamoxifen
b. Antiadnrogens
Flutamide
Cyproterone
c. Gonadotropin releasing hormone
Leuprolide
6) Immunosuppressents
7) Miscellaneous
a. Enzymes
Asparaginase
b. Biological response modifiers
c. Platinum coordination complexes
CisPlatin