Anti cancer drugs

Anti microbials are specific while anti cancer drugs are non specifics

Three common ADR
Alopecia
BM suppression
GIT mucositis






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Cell cycle

G0 phase
Quiescent phase

G1 phase
Prophase

S phase
Components for DNA synthesis
Folic acid
Purine
Pyrimidine
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Enzymes
Topoisomerase 1



G2 phase
Topoisomerase 2


M phase
Cell division






G1 phase

L aspariginase: enzyme that has anti cancer drugs, common toxicities
not seen with it. It causes hemorrhagic pancreatitis and
Hypercoagulation

Steroids


S phase
Antimetabolites
Camptothecins: irinotecan, topotecan


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G2 phase
Antibiotics: all Abx are non cell cycle specific except bleomycin

Epipodophyllotoxin: acting on topoisomerase 2
Etoposide
Teneposide


M phase
Taxanes: paclitaxal, docetaxal
Vinka alkaloids:Vincristine, vinblastine





Antimetabolites

Antifolates
Methotrexate
Permetrexate
Trimetrexate
Above two useful for mesothelioma
Palatrexate: T cell lymphoma



Purine
6 thioguanine
6 mercaptopurine
Fludaribine
Cladiribine: doc for hairy cell leukemia
Pentostatin freemedworld.com
All 3 above for hairy cell


Pyrimidine
Cytarabine( cytosine arabinoside)
5 fluoro uracil
Floxuridine
Gemcitabine
Capecitabine



Majority of anti metabolites have anti cancer and
immunosuppressant



Methotrexate
Most useful in trophoblastic disease: chorioCa

Mtx inhibits competitively dihydrofolate reductase
Over expression of dihydrofolate reductase is the reason for
resistance of mtx

Specific antidote : leucovorin or folinic acid
But it does not prevent neurotoxicity

Glucarpidase
Promotes the metabolism of mtx, thus can be used in mtx poisoning



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Uses: pharmacodynamics

Anti cancer
ChorioCa, doc
Breast Ca
Head and neck Ca
Osteosarcoma

Immunosuppressant
RA: 7.5 mg/ week, it's a DMARD's
Causes hepatotoxicity on long term use, thus periodic LFT needed


ADR
Myelosuppression
GI toxicity
Alopecia
Neurotoxic
Hepatotoxic
In acidic urine, form crystals causing crystalliria this alkalization and
hydration done to overcome it
Strong teratogenic and abortifacient
Sulfonamide also causes crystalluria








Antipurines
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6 mercaptopurine converted into 6 thiosinic acid by HGPRTase
Lesch nyhan syndrome: deficiency of HGPRTase

6 mercaptopurine undergoes inactivation by xanthine oxidase
Thus allopurinol will cause its toxicity as it inhibits xanthine oxidase

Tumor lysis syndrome follows anti cancer therapy
Causing
Hyperuricemia
Hypercalcemia

Thus allopurinol will be used
6 mercaptopurine dose need to be reduced

Newer drug febuxostat also inhibits xanthine oxidase





Fludarabine/ cladribine
Cladribine doc for hair cell leukemia
Also used for multiple sclerosis



Pentostatin
Inhibits adenosine deaminase
Also used in hairy cell leukemia



Pyrimidine antimetabolites
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All inhibit thymidylate synthetase

Most important drug is 5 FU

Systemic use of 5 FU
Colorectal Ca with levamisole( anti helminthic)

Topically
Keratosis, superficial basal cells carcinoma








Cytarabine
Aka Cytosine arabinoside

Most specific action on S phase

ADR
Cerebellar ataxia

Capecitabine: most common side effect is hand foot syndrome
Other causes of hand foot syndrome
5 FU
Doxorubicin
IL-2
Permetrexate
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Gemcitabine
Pyrimidine antimetabolites

Doc for pancreatic Ca

ADR
Myelosuppression
Flu like symptoms

Very potent radio sensitizer

Erlotinib can also be used for pancreatic cancer, tyrosine kinase inhibitor



Antibiotic anti cancer drugs

Plicamycin: side effect of hypocalcemia
Dactinomycin: radiation recall phenomena
Bleomycin: pulmonary fibrosis



Drugs

Actinomycin D( Dactinomycin)
Daunorubicin
Doxorubicin : broadest spectrum causes cardiomyopathy
Mitomycin freemedworld.com
Bleomycin
Mitoxantrone: aml, Ca prostate, MS
Mithramycin aka plicamycin: can cause hypocalcemia






Doxorubicin

Uses
AML

ADR
Most important is cardio toxicity, leading to heart failure
Doxorubicin in the presence of iron forms free radicals which injure
the myocardium
Dexrazoxane is the iron chelator used to minimize this

Trastuzumab also causes cardiomyopathy : monoclonal Ab used in
breast Ca








Bleomycin

Cell cycle specific antibiotic anti cancer drug acting on G2 phase
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Use
Germ cell tumor

ADR
Pulmonary toxicity
Mucocutaneous fibrosis

Bleomycin hydrolases not seen in lung and skin, thus toxicity seen

Type 1 cells
Necrosis/ destruction

Type 2 cells
Hyperplasia / Metaplasia


No myelo suppression by bleomycin
Vincristine also does not cause myelosupression











Urinary bladder Ca

BCG given intravesical freemedworld.com
for bladder Ca
It is an immunostimulant

Valrubicin is given for HCG resistant bladder Ca
Mitomycin: used to treat Hypoxic tumor cells, topically for
laryngotracheal stenosis by inhibiting fibroblast activity







Alkylating agent

Busulfan
Nitrosourea: lomustine, semustine, carmustine
Chlorambucil
Cyclophosphamide , ifosfamide
Melphalan, decarbazine, procarbazine, mechlorethamine, thiotepa

Mechlorethamine causes back vesicant
Treated by thiosulfate
If caused by vincristine, treated by hyaluronidase

Procarbazine causes disulfiram reaction

Procarbazine and melphalan will cause max secondary Ca

Decarbazine primarily attacks RNA, usually anti cancer drugs attack
DNA


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Nitrosourea very good drugs for brain tumor



Common points for all Alkylating agents

Alkylating agents attach to N7 guanine residue
They cause cross linking of DNA, abnormal base pairing and cause
DNA strand breakage

All are cell cycle non specific
All cause secondary neoplasia: most common are procarbazine and
melphalan
All causes sterility
All cause veno occlusive disease of liver: defibrotide given to
overcome this

Other secondary cancer causing drugs
Cisplatin
Alkylating agents
Both above cause after 4-5 years, delayed secondary cancer
Etoposide: early secondary cancer, within a year










Cyclophosphamide freemedworld.com
It is a pro drug
Active metabolites are
Phosphoride mustard
Aldo phosphamide
Acrolein: causes hemorrhagic cystitis

Immunosuppressive action
Doc for WG
Also used in nephrotic syndrome


ADR
Hemorrhagic cystitis
Treated by Mesna, it Inactivates the acrolein
Mercapto ethane sulfonic acid: Mesna


Uses of N acetylcysteine
Doc for paracetamol poisoning
Mucolytic
Radiocontrast poisoning
Hemorrhagic cystitis

Carboprost can also be given for treatment of hemorrhagic cystitis



Ifosfamide
Forms acrolein and chloroacetaldehyde

Chloroacetaldehyde causes RTA and neurotoxicity

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Nitrosoureas
Crosses BBB
Cause delayed myelosupression
Useful for brain tumor

Temozolamide also useful for brain tumors like glioblastoma
multiforme
Malignant melanoma
Levodopa CI in malignant melanoma as it is a precursor of melanin

IL-2 analogue Aldesleukin can also be used for malignant melanoma
Also used for RCC
Also useful for RCC
Sorafinib: also useful for HCC
Sunitinib: gastrointestinal stromal tumor
Bevacizumab




Multiple myeloma
Doc is melphalan
Other options are
Thalidomide
Lenolidomide freemedworld.com
Bortezomib: proteosome blocker, used for resistant and refractory
MM
Latest proteosome inhibitor: carfilzomib

Pomalidomide, derivative of thalidomide, also useful










Busulfan
In older days, considered a drug of choice for CML, now Imatinib
Also used for polycythemia Vera

ADR
Myelosupression
Pulmonary and dermatological toxicity
Adrenal insufficiency causing Addison's leading to hyper pigmentation
Hyperuricemia due to tumor lysis syndrome
Cataract
Gynecomastia






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Etomidate
General anesthetic
Also causes adrenal insufficiency
Vit C deficiency

N2O causes Vit B12 deficiency










Hormones used in anti cancer therapy

Premenopausal women with ER positive: SERM or SERD
Postmenopausal women with ER positive: aromatase inhibitor


Prostatic cancer
GnRH analogues
Anti androgens

Lymphoma
Steroids: cause apoptosis

Carcinoid tumor
Octreotide , controls secretory diarrhea
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Estrogen physiology
It stimulates CTZ area
Growth and development of reproductive organs
Cause breast, cervical, endometrial Ca
Prevent osteoporosis by inhibiting Osteoclast
Favorable lipid profile prevent atherosclerosis and MI
Decrease LDL, increase HDL
Promote synthesis of clotting factor: 7,9,10
Decreases antithrombin 3
Can cause DVT, pulmonary emboli
Over expression of clotting factors causes more venous thrombosis

Drug goes entero hepatic circulation, duration of action increases,
liver shows adenoma and cholestatic jaundice
Broad spectrum antibiotic inhibit entero hepatic circulation and
therapeutic failure, also by enzyme inducers



Estrogen acts as an agonist on endometrium causing Ca
Helps in osteoporosis
Causes breast Ca
Cardio protective
Increases memory and thinking ability

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Early problems
Vomiting
Headache as they are vasodilators
Late problems
DVT, pulmonary embolism
Ca











Selective estrogen receptor modulator

For premenopausal breast cancer
Tamoxifen
Toremifen
Doloxifen

Selective estrogen receptor downregulator
Fulvestrant
Used in SERM resistant pts





Tamoxifen freemedworld.com
Very good for premenopausal breast Ca

ADR
Cause vasodilation and flushing
May cause endometrial Ca
Promoting synthesis of clotting factor causing DVT



Raloxifene
Introduced for treatment of osteoporosis
Action on breast cancer and does not cause endometrial Ca
But the common problem of flushing and DVT





In Postmenopausal women, source of estrogen is peripheral
Aromatase enzyme
Convert androgens to estrogen from adrenals and adipose tissue



Aromatase inhibitors
Aminoglutethimide
Formestane
Exemestane
Vorozole
Fadrozole
Letrozole
Anastrozole
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Aminoglutethimide
Inhibits adrenal cortical hormone synthesis
Used for Cushing
Chemical adrenalectomy
Chemical pancreatectomy: strptozocin
Chemical defibrillator: bretyllium






SERM useful for DUB
Ormiloxifene
Aka Centchromin
Also used for non hormonal contraception: saheli

SERM for dyspareunia
Ospimefene


Progesterone antagonist

Mifepristone
MTP
Post coital contraception


Selective progesterone receptor modulator

Ulipristal
Post coital contraception
Effective after 5 days freemedworld.com







Prostate Ca

Anti androgens
Flutamide
Nilutamide
Bicalutamide
Enzalutamide
Cyproterone
Abiraterone



GnRH analogues
When given in pulse, agonist
If given continuous, antagonist

Initially it may cause increase FSH and LH
Thus flare up
LH causes increased testosterone




GnRH analogues
Leuprolide
Goserelin freemedworld.com
Busorelin
Naferelin
Desorelin
Histrelin
Tritprelin

All are given SC

Busorelin and Naferelin can be given intra nasally
Goserelin can be given SC implantation

All cause initial flare up
Histamine release

GnRH antagonists
Oganirelix
Ocetrorelix
Abarelix
Degarelix

No initial flare up and histamine release


Drugs having histamine releasing property
D tubocurarine , thus unsafe in asthmatic, also cause fall in BP
Morphine, thus used in LVF as vasodilates
Desferioxamine
Amphotericin
Polymixin B
Atropine
Vancomycin: red man syndrome, antihistamines and steroids given
prior to vancomycin and be ready with emergency drugs for
anaphylaxis freemedworld.com









Vinca alkaloids

Vinca rosea: vincristine, vinblastine
Vinorelbine: semisynthetic derivative of vinblastine
Act in M phase

Microtubulin structure undergoes polymerization forming mitotic
spindle
Then spindle undergoes separation into daughter cells

Vinca alkaloids inhibit polymerization, thus inhibiting formation of
mitotic spindle
Taxane causes persistent polymerization, spindle is not allowed to
divide: paclitaxel



ADR
Neurotoxic: peripheral sensory neuropathy
Max among all anti cancer drugs
Pin prick sensation
SIADH
Skin vesicant treated by hyaluronidase
No myelosupression with vincristine but seen with blastine
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Taxanes
Paclitaxel
Docitaxel

Bark of pacific yew tree
Stabilize polymerization of tubulins

Both cause myelosupression and neurotoxicity





Ixabepilone
New drug acting on M phase
Promote stabilization of tubulin
Used for advanced breast Ca







Monoclonal Ab

Mab= monoclonal Ab

Preceding two letters
Tell about origin freemedworld.com
Zu= humanized origin
Xi= chimerical origin

Preceding two letters
Tell about target
Tu= tumor
Li= lowering immunity: immunosuppressant
Ci= circulation
Vi= viral




Uses
HER 2/ neu positive breast Ca

Majority monoclonal Ab given IV
Thus cause infusion related toxicity
thrombophlebitis, fever, chills, rigor

Trastuzumab
Also causes cardiomyopathy

Pertuzumab
Her 2/ neu positive receptor breast Ca





Ritumixab
CD20 Ag and B cell
Used in B cell lymphoma, RA, AIHA
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ADR
Infusion reaction
PML progressive multifocal leucoencephalopathy




Alemtuzumab
Target
CD 52
B cell and T cell

Uses
B and T cell lymphoma

ADR
Infusion reaction
Immunosuppression


Cetumixab

Target
EGFR

Use
Colorectal Ca

ADR
Infusion reaction


Bevacizumab freemedworld.com

Target
VEGF

Uses
Metastatic colorectal Ca along with 5 FU
RCC
Diabetic neuropathy: controls retinal hemorrhage

ADR
HT and CHF
Pulmonary hemorrhage
Both cardiac and lung problems






Cisplatin
Highest emetogenic drug
Dose limiting toxicity is nephrotoxicity: manifesting as hypokalemia ,
hypomagnesimia, hypocalcemia, hypophosphatemia
Mannitol given along with cisplatin to decrease nephrotoxicity
Amifostine is the doc to be used though
Ototoxic
Neurotoxic
Used for
Cervical and ovarian Ca


Carboplatin
Myelosupression freemedworld.com

Oxaliplatin
Pharyngo laryngeal dysaesthisia, paresthesias, neurotoxicity
Circumoral parasthesia
Lignocaine
Ritonavir










Tyrosine kinase inhibitors
Ending with nib
All given orally

Imatinib
Doc for CML
Good drug for GIST: target is C-KIT


In case of Imatinib resistant cml
Dasatanib and nilotinib.


Gefitinib
Used for
Metastatic non small cell lung Ca
Erlotinib in addition good for pancreatic cancer, given along with
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gemcitabine


Lapatinib
For breast Ca
Inhibits tyrosine kinase asso with EGFR and Her2 neu receptor



Sorafenib
RCC
HCC

Sunitinib
RCC
GIST


All nib undergo metabolism by CYP3A4







Miscellaneous drugs in cancer

Thalidomide
Used for emesis and sedation

Used for
MM freemedworld.com
Erythema nodosum leprosum

Available in R and S forms
R responsible for therapeutic use and Teratogenicity
S responsible for sedation

ADR
Constipation
Peripheral sensory neuropathy




Lenalidomide
Derivative of thalidomide
Used for MM, myelodysplastic syndrome and sickle cell anemia( doc
is hydroxyurea)






Demileukin deftitox
Combo of IL-2 with Diphtheria toxin
Used for Cutaneous T cell lymphoma
Newer drug for cutaneous T cell lymphoma
Vorinostat and romidepsin: histone deacetylase enzyme blocker




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Vaccine for cancer

Cervical Ca
Gardasil
Cervarix









Protectants

Myelosupression

Neutropenia
Treated by
Colony stimulating factors

G-CSF
Filgrastin
Pegfilgrastin
Lenograstin


Sargramostin(GM-CSF), molgrastim
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TREATMENT OF ANEMIA
EPOIETIN: recombinant erythropoietin
Darbopoietin

Peginesatide: erythropoietin receptor stimulant




Thrombopoeitic growth factors

Oprelvekin: IL-11
Thrombopoeitin


Romiplostim , useful for ITP, given SC
Eltrombopag, useful for ITP, given oral






How to control vomiting

Best choice is 5 HT3 antagonist
Ondansetron
Granisetron
Dolosetron: May cause QT prolongation
Palonosetron: highly selective for 5HT3
Others have slight D2 activity
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Adjuvants for better effect
Domperidone: D2 blocker
BZD
Steroids


Cannabinoid having anti emetic property
Nabilone
Dronabinol

5 HT3 blockers are doc for early and anticipatory vomiting

After 2-3 days of anti cancer therapy
Late phase vomiting: Aprepitant
Neurokinin 1 antagonist

Alosetran is used for diarrhea but causes ischemic colitis
Thus used in diarrheal dominant IBS
It is a 5HT3 antagonist
Used only in females










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Immunomodulator
Can be

Immunosuppressant drugs
Glucocorticoids: inhibit IL 1,6
Cyclosporin, tacrolimus, Sirolimus, everolimus
Cytotoxic drugs:
Purine analogues:
Azathioprine
Mycophenolate

Pyrimidine analogue
Leflunomide

Folate analogue
Methotrexate

Cyclophosphamide





Ab having immunosuppressive activity

Lymphocyte immunoglobulin( LIG, ATG)
Rh(D) immunoglobulin
Monoclonal Ab
Daclizumab and basiliximab: IL-2 inhibitor
Infliximab : used for RA and Crohn's disease

OKT3: muromonab
Side effect of cytokine release syndrome
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Immunostimulants

Cytokines
Aldesleukin
Used for RCC and MM
Interferon Y: chronic Granulomatous disease

BCG vaccine
Intravesical therapy
Superficial bladder Ca

Thymosine

Levamisole



Cyclosporin
CD4 inhibitor



Immunomodulator for RA
Leflunomide freemedworld.com
Infliximab
Etanercept
Adalimumab
Above three are TNF alpha blocker
Anakinra
Tenidap Na
Abatacept




Cytokines

Pro inflammatory
TNF alpha
IL-1
These are chemical bombs of tissue destruction
TNF alpha blockers
Infliximab IV, periodic LFT mandatory
Adalimumab SC
These are straight antagonist

Etanercept : forms soluble receptor, SC

All TNF alpha blockers are immunosuppressive
Thus ppd test done before giving it

Two other are
Golimumab
Certolizumab
Both given SC

All can cause injection site reaction
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IL-1
Taken care by IL-1 receptor antagonist
We prepared
Analogue of interleukin 1 receptor antagonist: ANAKINRA

LEFLUNOMIDE
Acts on dihydroorotate dehydrogenase DHOD
Cause hepatotoxicity
Teratogenic, CI in pregnancy

Teriflunomide
Inhibits DHOD


Tenidap Na
IL-1 synthesis inhibitor

Disease modifying anti arthritic drug
Diacerin( IL-1 antagonist)
Licofelone ( combined cox- lox inhibitor)



Mycophenolate
Acting by inhibiting inosine monophosphate dehydrogenase



Alefacept:
Used for psoriasis
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For HPV induced Condylomata accuminata: imiquimod
resiquimod: HSV


Eculizimab: for PNH, target is complement component C5

Ibalizumab: HIV

Efalizumab: RA