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.
