Anticancer and immunopharm Flashcards
Cyclophosphamide
• Alkylating agent. Nitrogen mustard
• Needs to be activated by hepatic enzymes
• Metabolism gives a toxic compound called acrolein
• Used in a wide variety of neoplastic diseases (combination therapy).
– Adrenal cortex cancer
– Bladder cancer
– Bone cancer
– Cervical cancer
– Endometrial cancer – Lung cancer
– Non-hodgkins lymphoma, etc.
SE • Bone marrow suppression • Immunosuppression • Hemorrhagic cystitis • Nausea and vomiting • Alopecia • Gonadal failure- amenorrhea & sterility • SIADH • Irritation of the bladder by acrolein leading to hemorrhagic cystitis
• Prevention:
– Administration of MESNA (a sulfhydryl compound) which inactivates acrolein.
– Maintaining urine output of > 3L/day
Ifosfamide
- Mechanism of action & ADR similar to cyclophosphamide
- More potent than cyclophosphamide
- More potential to cause hemorrhagic cystitis
- Prior administration of MESNA is a must for each dose
Other nitrogen mustards
- Mechlorethamine- Highly vesicant, used in nonhodgkins lymphoma
- Melphalan-Used in multiple myeloma
- Chlorambucil-used in CLL
Busulfan
- Alkylating agent. It is sometimes used in chronic myelogenous leukemia.
- It causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation.
Carmustine, Lomustine, Semustine
• Nitrosureas. Alkylating agent. All nitrosoureas cross the blood brain barrier
MOA
The chloroethyl moiety of nitrosoureas alkylates nucleic acids and proteins, producing single-strand breaks and interstrand cross-linkage of DNA
- Carmustine (BCNU) and Lomustine (CCNU) have high lipophilicity that facilitates CNS entry.
- Are used as adjuncts in the treatment of brain tumors.
- Toxicities include GI distress, delayed myelosupression, and CNS dysfunction.
Dacarbazine
- Alkylating agent. Synthetic drug; requires activation by liver microsomal system.
- Used in hodgkins disease, soft tissue sarcoma and melanoma.
- Adverse effects: Myelosuppression, nausea & vomiting
Procarbazine
– Methylhydrazine derivative. Alkylating agent. – Active in Hodgkin's disease (combination therapy) – Teratogenic, mutagenic & leukemogenic. – Side effects: • Nausea, vomiting, myelosuppression • Hemolytic anemia • Pulmonary effects • Peripheral sensory neuropathy • Disulfiram like reaction.
Cisplatin, carboplatin, oxaliplatin
• Platinum compounds. Alkylating agents.
• Minimal bone marrow suppression
• Uses: Wide range of solid tumors like germ cell tumors, ovarian cancer, non small cell lung cancer, etc.
• Adverse effects:
– Severe nausea and vomiting due to intense stimulation of CTZ (Chemoreceptor Trigger Zone)
– Neurotoxicity- peripheral neuropathy and deafness (cochlear nerve damage)
– Nephrotoxicity- leads to electrolyte imbalance
Cisplatin SE
• Cisplatin induced nephrotoxicity. Dose-limiting toxicity of cisplatin
Treatment:
• Osmotic diuresis with mannitol
• Forced chloride diuresis with 0.1% NaCl
• Administration of amifostine, a cytoprotective agent which gives Thiol (-SH) compound on activation inactivates free radicals generated by cisplatin.
• Amifostine decreases the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression.
• Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeated doses of cisplatin for advanced ovarian cancer and non-small- cell lung cancer
Carboplatin, Oxaliplatin
- Has more acceptable toxicity profile than cisplatin - less nephrotoxic, less neurotoxic & less emetogenic.
- More myelosuppression than cisplatin.
Methotrexate
•Mechanism of action: Inhibits the enzyme dihydrofolate reductase which converts dihydrofolic acid into tetrahydrofolic acid.
Uses: • Choriocarcinoma • Acute Lymphoblastic Leukemia • Burkitt’s lymphoma • Osteosarcoma • Breast cancer
SE
• Common: Bone marrow suppression, immune- suppression, mucositis, & alopecia.
• Renal damage: due to crystal deposition in kidney tubules (adequate hydration prevents this complication)
• Pulmonary toxicity especially if given to children.
• Hepatic fibrosis when given for long period.
Leucovorin rescue
• Leucovorin or Folinic acid
• Used in cases of over- dosage or in high-dose methotrexate protocols.
• Leucovorin provides cells a source of reduced folate, there by overcoming blockade by methotrexate.
6-mercaptopurine
- Purine antagonist. 6-MP is converted into 6-Thioinosinic acid (TIMP)
- TIMP inhibits de novo purine synthesis.
- TIMP also blocks formation of AMP & GMP.
• Use: Acute Lymphocytic Leukemia • Adverse effects – Bone marrow suppression – Hepatotoxicity – Nausea & vomiting
- 6-MP is metabolised to thiouric acid by xanthine oxidase.
- Allopurinol, is a xanthine oxidase inhibitor, used to reduce uric acid formation.
- Dose of 6-MP must be reduced if co- administered with allopurinol.
6-thioguanine
• Purine antagonist
• Mechanism of Action: inhibits DNA & RNA synthesis by decreasing intracellular GMP concentration.
• Clinical Use: Treatment of acute lymphoid leukemia. No drug interaction with allopurinol.
• Adverse effects
– Bone marrow suppression
– Hepatotoxicity
– Nausea & vomiting
5-fluorouracil
- Pyrimidine antagonist. 5-FU gets converted into deoxyribonucleotide which inhibits thymidylate synthase.
- DNA synthesis is inhibited due to thymidine deficiency.
- 5-FU is also incorporated into RNA.
- Supplementing leucovorin (folinic acid) along with 5-FU leads to incorporation of more 5-FU metabolite into RNA- generation of more nonfunctional RNA.
- Addition of leucovorin increases the cytotoxic effects of 5-FU
• Adverse effects: – Myelosuppression – Mucositis – Skin exfoliation on palm and feet “hand-foot syndrome” – Alopecia
• Use:
– Systemically: Adenocarcinomas
– Topically: Skin cancer
Capecitabine
- Pyrimidine antagonist. Oral prodrug of 5-FU
- Converted into 5-FU by thymine phosphorylase inside the tumor cells.
- Use: metastatic breast cancer & colorectal cancer.
- Adverse effects: similar to 5-FU
Gemcitabine
- Pyrimidine analog. Competes with cytidine. Incorporated into DNA, inhibits chain elongation
- Adverse effects: Myelosuppression, alopecia, flu like symptoms & elevation of liver enzymes.
- Uses: Pancreatic cancer, non small cell cancer of lung, ovarian cancer, etc.
Cytarabine
- Pyrimidine antagonist. Biotransformed to active forms: Ara-CTP competitively inhibits the enzyme DNA polymerase.
- Use: AML for induction & CML in blast crisis
- Adverse effects: Myelosuppression (common) & ataxia
Vincristine, Vinblastine, Vinorelbine
- Vinca alkaloids
- MOA: Bind to  B-tubulin and prevents formation of microtubules. Cells are arrested in metaphase (M phase).
• Use:
– Vincristine - Hodgkin’s lymphoma
– Vinblastine - testicular cancers
– Vinorelbine - Non small cell lung cancer
• Major adverse effects
– Vincristine - Neuropathy (myelosuppression is
minimal, considered as bone marrow sparing drug)
– Vinblastine - Myelosuppression
– Vinorelbine - Granulocytopenia.
Paclitaxel, Docetaxel
- MOA: enhances tubulin polymerization and stabilizes microtubules in polymerized state. Cell is arrested in metaphase (M phase)
- Uses: ovarian & breast cancer.
• Adverse effects:
– Paclitaxel- severe allergic reaction attributed to cremophor vehicle, neutropenia & alopecia is universal.
– Docetaxel- Skin toxicity and fluid retention leading to pleural and peritoneal effusions.
Etoposide, Tenoposide
• Acts at late S and early G2 phase of cell cycle
• Mechanism of action:
– Topoisomerase II inhibition.
– Prevents re-ligation of DNA strand breaks.
• Use: Germ cell tumor, AML & lung cancer
• Adverse effects:
– Myelosuppression
– Definite association between etoposide use and leukemia (in survivors)
Topotecan, Irinotecan
• Mechanism of action: Topoisomerase I inhibition
• Use:
– Topotecan - Metastatic ovarian cancer (cisplatin-
resistant)
– Irinotecan - Colon and rectal cancer
• Adverse effects
– Topotecan -Neutropenia, thrombocytopenia, anemia
– Irinotecan - Severe diarrhea, myelosuppression (caution in patients with Gilbert’s syndrome)
Bleomycin
- Cell cycle specific agent: acts at G2 Phase
- Bleomycin is inactivated by cellular metabolism via enzyme bleomycin hydrolase.
- Pharmacokinetics: Eliminated exclusively by kidney.
- Induction of free radical mediated DNA strand breaks.
- Reduced iron mediates the reduction of molecular oxygen into damaging free radicals
• Clinical Use: Hodgkins lymphoma, testicular cancer, kaposi sarcoma, etc.
• Toxicity: Seen in tissues low in enzyme bleomycin hydrolase.
– Pneumonitis followed by PULMONARY FIBROSIS – Skin reaction
– Raynauld’s phenomenon
– Retroperitoneal fibrosis
• Does not have significant effect on bone marrow (considered as bone marrow sparing drug)
Doxorubicin, Daunorubicin
- Inhibition of topoisomerase II leading to DNA breaks
- Formation of highly reactive oxygen free radical species which damages DNA, cell membrane, proteins, etc.
- Alters membrane fluidity and ion transport.
• Uses: Has broad anti-tumor activity. Breast cancer, AML, lymphomas, sarcomas, etc.
• Adverse effects:
– CARDIOTOXICITY
– Myelosuppression
– Nausea, vomiting, alopecia & mucositis
– Erythema at sites of prior radiation “Radiation recall reaction”
– Highly vesicant
Anthracyclines induced cardiotoxicity
• Free radical damage is thought to be mechanism.
• Heart is vulnerable as it has limited capacity to neutralize free radicals.
• Dexrazoxane, an Iron chelating agent is used reduce free radical induced damage.
Dactinomycin
• Cell cycle nonspecific agent
• Mechanism of action: Binds to DNA noncovalently.
• Used in Wilm’s tumor and sarcomas.
• Highly vesicant: Extravasation can lead to
necrosis to the tissue.
• Erythema at sites of prior radiation “Radiation recall reaction”.
Dexamethasone, Hydrocortisone, Prednisone, Prednisolone
• Acute Lymphocytic Leukemia, Hodgkins lymphoma, non-hodgkins lymphoma, multiple myeloma, etc.
• Palliative care to improve feeling of well being.
• Used in spinal cord compression due to
metastasis to relieve edema.
• Management of autoimmune anemia and thrombocytopenia.
Diethylstilbestrol, Ethinylestradiol
- Used in prostate cancer
- Contraindicated in patients with breast & endometrial cancers.
• Adverse effects:
– Increased risk of thromboembolism, migraine,
cholestasis and mood changes.
– Gynecomastia & impotence when administered to men.
Tamoxifen, Raloxifene
- Used as primary therapy for metastatic breast cancer in both men and postmenopausal women
- Decreases the incidence of breast cancer in women who are at high risk for developing the disease.
- Selective Estrogen Receptors Modulators: They exhibit agonistic action in some tissue and antagonists in other tissues.
- Tamoxifen: Antagonist effect on breast tissue but agonistic effect on endometrium & bone.
- Raloxifene: Antagonist at breast & endometrium but agonist at bone
• Adverse effects:
– Hot flushes and thrombosis.
– Fluid retention
– Risk of endometrial cancer when used for long period.
Aminogluthethimide
- Reversible steroidal inhibitor of adrenal steroid synthesis at the first step (desmolase), conversion of cholesterol to pregnenolone
- Inhibits the extra-adrenal synthesis of estrone and estradiol.
- Inhibits the enzyme aromatase that converts androstenedione to estrone.
Therapeutic Use:
• ER-positive metastatic breast cancer
• Toxicity – Adrenal insufficiency – Dizziness – Lethargy – Visual blurring – Rash
Anastrozole, Letrozole
- Selective non-steroidal reversible inhibitor of aromatase enzyme
- Use: Treatment of advanced estrogen receptor positive breast cancer that is resistant to tamoxifen
- Adverse effects: Hot flushes & headache.
Exemestane, Formestane
- Steroidal non-reversible inhibitors
- Use: Advanced estrogen receptor positive cancer
- Adverse effects: Mood changes, acne and hair growth.
Hydroxyprogesterone, Megestrol
• Progestins. Used in endometrial cancer • In palliative care: To improve appetite in terminally ill cancer patients. • Adverse effects: – Weight gain – Depression – Edema, acne – ↓HDL
Fluooxymesterone, testosterone
• Androgens. Used occasionally in palliative care to improve feeling of well being and appetite.
Leuprolide, Goserelin
• Gonadotropin-releasing analogues
• Continuous dose (not pulsatile dose) will
produce reversible medical castration.
• Continuous administration leads to decreased release of LH & FSH.
• Initial flare-up of androgen dependent cancer may occur.
• USE:
– Prostate cancer
– Some times for fibroid uterus
• ADR: Decreased bone mass, hot flushes, initial tumor flare up, impotence, etc.
Flutamide
• Androgen receptor blocker
– Antagonizes androgenic effects
– Approved for the treatment of prostate cancer
– Given with GnRH agonists to prevent initial tumor flare-up
• Adverse effects: Gynecomastia & GI distress
Hydroxyurea
- An analog of urea
- Inhibits the enzyme ribonucleotide reductase resulting in the depletion of deoxynucleoside triphosphate pools, thereby inhibiting DNA synthesis
- S-phase specific agent
• Use:
– Treatment of melanoma and chronic myelogenous leukemia
– Used in sickle cell disease to increase fetal hemoglobin (HbF) production
• Adverse effects:
– Leukopenia (reversible upon discontinuation of drug)
– Mild GI toxicity
– Mild dermatologic changes with prolonged therapy
L-asparaginase
- Causes catabolic depletion of serum asparagine to aspartic acid and ammonia
- This results in reduced blood glutamine levels and inhibition of protein synthesis
- Neoplastic cells require external source of asparagine
- Use: Childhood acute leukemia
SE • Hypersensitivity reactions (Can cause anaphylactic shock) • Hemorrhage • Hyperglycemia • Headache • Pancreatitis
Arsenic trioxide
• Used in treatment of acute pro-myelocytic leukemia.
• In PML/RAR-α positive AML, arsenic trioxide causes differentiation of leukemic cells.
• Adverse effects:
– Headache
– Cardiac arrhythmias
– Fluid retention
– Increases risk of skin cancers
IFN
• Produced by recombinant DNA technology
• Mechanism of action: Not clearly understood
– INF-α stimulates natural killer cells
– Increases the expression of HLA molecules on tumor cells
• Uses:
– INF-2α : CML, hairy cell leukemia, kaposi sarcoma, etc.
– INF-2β: Melanoma, follicular lymphoma, AIDS related Kaposi sarcoma, etc.
• Adverse effects: fever, myalgia, headache, loss of appetite, depression, etc.
Imatinib
- Inhibit tumor tyrosine kinase activity.
- Used in treatment of BCR-ABL positive CML, ALL, & GIST
- Adverse effects: Fluid retention, edema, hepato-toxicity, thrombocytopenia, etc.
Gefitinib
- Mechanism of action: Inhibits EGFR signal transduction.
- Used in treatment of non small cell lung cancer
- Adverse effects: Acne like skin lesions, nausea, diarrhea, etc.
Cyclosporine
- Binds to intracellular protein “cyclophilin” and inhibits calcineurin.
- Prevents the activation of NFAT (Nuclear Factor of Activated T cell), which is necessary for cytokine production.
- Grape fruit juice increases absorption by inhibiting MDR (p-glycoprotein) in small intestine.
- Metabolized by CYP3A system, prone for drug interactions.
SE
• Major adverse effect: Nephrotoxicity. hepatotoxicity, hypertension, dyslipidemia, hyperglycemia, tremor & hyperkalemia.
• Chronic use: Increase incidence of lymphoma & squamous cell cancer of skin
• Other side effects: Gum hyperplasia & hirsutism
DRUG INTERACTIONS
• CYP enzyme inducers: Rifampin, phenobarbital, etc.
• CYP enzyme inhibitors: Ketoconazole, erythromycin, omeprazole, etc.
• Nephrotoxicity: Aminoglycosides (Ex: amikacin), Amphotericin B, etc.
• Hyperkalemia: Spironolactone, Potassium supplement, etc.
Tacrolimus (FK506)
- Macrolide antibiotic, 100 times more potent than cyclosporine
- Binds to FK-506 binding protein and the complex inhibits calcineurin.
- Adverse effects: Similar to cyclosporine, but more likely to cause neurological side effects. No gum hyperplasia or hirsutism.
- Absorption is bile dependent, metabolized by CYP3A system.
Sirolimus (rapamycin)
- Inhibits mammalian Target of Rapamycin (mTOR) and inhibits the action of IL-2.
- Sirolimus-eluting coronary artery stents are effective in preventing re-stenosis after coronary angioplasty.
- ADR: Hyperlipidemia, nephrotoxic when combined with cyclosporine.
Corticosteroids
- Inhibit cell cycle & induce apoptosis in activated T cells (Lympholytic action), hence prevent proliferation of activated T-Cells.
- Inhibit both cellular and humoral immune response.
- Prednisone is commonly used.
- ADR: Adrenal suppression, osteoporosis, hypertension, peptic ulcer, muscle wasting, Cushing features, etc.
Mycophenolate mofetil
- Prodrug, rapidly converted into mycophenolic acid.
- Mechanism of action: Inhibits IMP dehydrogenase [an enzyme necessary for guanosine (purine) synthesis]
- Suppresses both T-cell and B-cell activation.
- Adverse effects: Diarrhea and myelosuppression (neutropenia)
Cyclophosphamide
- An anti-cancer drug (alkylating agent).
- Kills proliferating lymphoid cells.
- Useful in Wegener’s granulomatosis, SLE & other autoimmune diseases.
- ADR: Hemorrhagic cystitis (Can be prevented by prior administration of MESNA) and bone marrow suppression.
Azathioprine
- An anti-cancer drug (anti metabolite)
- Prodrug, converted into 6-mercaptopurine.
- Metabolized by xanthine oxidase, an enzyme involved in uric acid production.
- Allopurinol (used to reduce uric acid production) inhibits xanthine oxidase.
- Dose reduction is necessary when co-administered with allopurinol.
- Useful in renal transplantation and autoimmune diseases
Methotrexate
• Used in treatment of rheumatoid arthritis.
•Mechanism of Immune suppression:
Aminoimidazolecarboxamide ribonucleotide (AICR) transformylase & thymidylate synthase.
• ADR: Bone marrow suppression, mucositis, hepatic fibrosis, etc.
Muromonab
- Anti CD3 antibody
- Used in treatment of acute graft rejection.
- Kills only T lymphocytes, hence selectively affect cell mediated immunity.
- ADR: Hypersensitivity reactions like anaphylaxis and serum sickness.
Daclizumab, Basiliximab
- Monoclonal antibodies against IL-2 receptor
- Daclizumab = entire Ab, Basiliximab = Fab
- Peri-operative use during transplantation.
Rho(D) Immune globulin (RhoGAM)
- Human IgG antibody against Rh antigen.
- Prevents primary immune response to Rh antigen on fetal red blood cells in Rh negative mothers.
- Prevents hemolytic disease of newborn in subsequent pregnancies.
- Should be administered to Rh negative patients within 72 hours of delivery or termination of pregnancy.
Aldesleukin
• Recombinant IL-2
• Activates cytotoxic T lymphocytes and Natural
killer cells
• Useful in treatment of renal cell cancer
IFNs
- Interferon-α-2a: Useful in treatment of Kaposi sarcoma, malignant melanoma, Hepatitis B & C
- Interferon –β-1b: Useful in treatment of multiple sclerosis
- Interferon  1b: Useful in treatment of chronic granulomatous disease.
Rituximab
• Monoclonal antibody against CD20 antigen, useful in CD20 tumours like non-hodgkins lymphoma, CLL, etc.
Citiuximab
• Monoclonal antibody against EFGR, used in colorectal cancer treatment.
Abciximab
- Monoclonal antibody against glycoprotein IIb/IIIa.
- Prevents thrombus formation.
- Used in percutaneous coronary artery intervention.
BCG (Bacillus Calmette-Guerin) vaccine
- Live attenuated vaccine against tuberculosis.
- Administered intravesically after resection of superficial bladder cancer.
- Should not be used in immunocompromised patients.
Thalidomide
• An Immunomodulator
• Decreases TNF-α production, enhances cell
mediated immunity, has anti-angiogenic effect.
• First line drug in the treatment of multiple myeloma
• Also useful in treatment of aphthous ulcers, lepra reaction and wasting syndrome in AIDS & terminal cancer patients.
SE
• Teratogenic: phocomelia (sealed limbs deformity)
• Neuropathy, constipation, DVT, and sedation.
