Anti-Neoplastic Agents

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  • Alkylating agents
    • Mechanism of action :
      • Clinically useful alkylating agents have a nitrosourea, bis-(chloroethyl)amine, or ethylenimine moiety.
      • The electrophilic center of these agents becomes covalently linked to the nucleophilic centers of target molecules.
      • Alkylating agents target the nitrogens (especially the N-7 of guanine) and oxygens of purines and pyrimidines in DNA
      • This leads to abnormal base pairing, depurination (followed by DNA chain scission), ring cleavage, and DNA strand crosslinks.
      • Nitrosoureas can also cause carbamylation
      • cells are most susceptible to alkylation in late G1 to S phases (MCQ)
    • Acquired resistance can involve
      • increases in DNA repair processes
      • reduction in cellular permeability to the drug
      • increased metabolism
      • production of glutathione (and other molecules containing thiols), which neutralizes alkylating agents by a conjugation reaction that is enzymatically catalyzed by glutathione S-transferase.
    • parenterally administered alkylating agents , except cyclophosphamide,  are direct vesicants and can damage tissue at the injection site.
    • Some degree of leucopenia occurs at adequate therapeutic doses with all oral alkylating agents.
    • The dose-limiting toxicity is bone marrow suppression. (MCQ)
    • Alkylating agents are also highly toxic to dividing mucosal cells, causing oral and gastrointestinal (GI) ulcers (MCQ)
    • Most of these agents also cause nausea and vomiting, which can be minimized by pretreatment with 5-HT3 antagonists
    • Most alkylating agents can cause sterility, and alopecia is common. (MCQ)
    • Patients with xeroderma pigmentosa are hypersensitive to alkylating agents. (MCQ)
    • Alkylating agents are mutagenic and can cause secondary cancer (e.g., leukemia) and sterility later in life. (MCQ)
  • Nitrogen mustards : bifunctional alkylating agents
    • Mechlorethamine
      • Mechlorethamine is extremely hygroscopic and unstable
      • The active drug is present only for minutes.
      • Used primarily in the MOPP regimen to treat Hodgkin disease (MCQ)
      • Leukopenia and thrombocytopenia are dose-limiting toxicities
      • repeat courses of treatment are given only after marrow function has recovered.
    • Cyclophosphamide and ifosfamide
      • Cyclophosphamide may be administered orally, IV, or intramuscularly
      • Mechanism of action
        • It is metabolically activated to 4-hydroxycyclophosphamide,
        • 4-hydroxycyclophosphamide is nonenzymatically cleaved to aldophosphamide
        • In tumor cells aldophospamide is cleaved to
          • phosphoramide mustard, which is toxic to tumor cells
          • acrolein, the agent suspected to cause hemorrhagic cystitis.
      • Cyclophosphamide is used to treat
        • lymphomas, leukemias
        • mycosis fungoides, multiple myeloma (MCQ)
        • retinoblastoma, breast and ovarian carcinoma,
        • small cell lung cancer.
      • Adverse effects
        • Cyclophosphamide has less incidence of thrombocytopenia than mechlorethamine, immunosuppression is still the most important toxic effect.
        • The metabolite acrolein may result in hemorrhagic cystitis (MCQ)
          • this effect can be prevented by coadministration of the sulfhydryl compound 2-mercaptoethanesulfonate (MESNA) (MCQ)
          • neutralizes acrolein at acidic pH in the urine
        • Reversible alopecia often occurs (MCQ)
        • nausea and vomiting are common.
      • Used in lupus nephritis,and arteritis. (MCQ)
      • Ifosfamide
        • is a cyclophosphamide analog
        • less potential to cause hemorrhagic cystitis
        • CNS and urinary tract toxicity limit its use to testicular cancer, stem cell rescue
      • Melphalan and chlorambucil
        • derivatives of nitrogen mustard
        • administered orally.
        • Melphalan is often used to treat multiple myeloma and carcinoma of the ovary. (MCQ)
        • The toxicity of mephalan is related mostly to myelosupression (MCQ)
        • Nausea and vomiting are infrequent
        • there is no alopecia. (MCQ)
      • Chlorambucil
        • slowest-acting nitrogen mustard
        • agent of choice in the treatment of chronic lymphocytic leukemia, some lymphomas, and Hodgkin disease (MCQ)
        • It produces less severe marrow suppression than other nitrogen mustards. 
    • Alkylsulfonates :busulfan
          • selectively myelosuppressive
          • inhibits granulocytopoiesis.
          • administered orally
          • used to treat chronic myelogenous leukemia and other myeloproliferative disorders. (MCQ)
          • produces adverse effects related to myelosuppression
          • It only occasionally produces nausea and vomiting.
          • In high doses, it fatal pulmonary fibrosis, ‘‘busulfan lung.’’ (MCQ)
    • Nitrosoureas
        • Carmustine,lomustin,and semustine
          • Carmustine, lomustine, and semustine are highly lipophilic
          • they cross the blood–brain barrier
          • Nitrosurea can carbamylate intracellular molecules.
          • These agents are given orally except for carmustine,which is administered IV.
          • Carmustine, lomustine, and semustine are useful in Hodgkin disease and other lymphomas, as well as in tumors of the brain (temozolomide is preferred agent now for tumors of brain) (MCQ)
          • These agents are markedly myelosuppressive, but with delayed effect, possibly up to 6 weeks.
          • Use of these agents may also result in renal failure.
        • Streptozocin
          • Useful for the treatment of pancreatic islet cell carcinoma and carcinoid. (MCQ)
          • This agent is not myelosuppressive
          • Nausea and vomiting almost always occur
          • Renal toxicity is the dose-limiting effect.
    • Ethylenimine: thiotepa (triethylene thiophosphoramide)
          • converted rapidly by liver mixed- function oxidases to its active metabolite triethylenephosphoramide (TEPA)
          • it is active in ovarian cancer(MCQ)
          • Myelosupression is a major toxicity.
    • Triazines:dacarbazine and tetrazines:temozolomide
        • Dacarbazine
          • activated in the liver to a cell killing methylating metabolite.
          • administered IV
          • primary component of the ABVD regimen (adriamycin, bleomycin, vinblastine, and dacarbazine) to treat Hodgkin disease, malignant melanoma, and soft tissue sarcomas. (MCQ)
          • Dacabazine is moderately myelosuppressive
          • Nausea and vomiting occur in 90% of patients.
          • Flu-like symptoms also occur.
        • Temozolomide
          • acts similarly to dacarbazine.
          • administered orally
          • primarily used to treat refractory anaplastic astrocytoma, such as glioblastoma multiforme; malignant melanoma; and uterine leiomyosarcoma. (MCQ)
          • toxicities are mainly hematologic and gastrointestinal.
  • Anti metabolites
    • S-phase–specific drugs (MCQ)
    • structural analogues of essential metabolites
    • interfere with DNA synthesis.
    • Myelosuppression is the dose-limiting toxicity for all drugs in this class. (MCQ)
  • Methotrexate
    • Mechanism
      • a folic acid analogue
      • inhibits dihydrofolate reductase (DHFR). (MCQ)
      • This reduces the pool of tetrahydrofolate required for the conversion of deoxyuridylic acid (dUMP) to deoxythymidylic acid (dTMP), and consequently, N5,N10-methylenetetrahydro- folate is not formed. (MCQ)
      • The net result is indirect inhibition of DNA synthesis.
      • Methotrexate also inhibits RNA and protein synthesis. (MCQ)
    • Administered orally,IV,intramuscularly,or intrathecally.
    • It is transported into cells by folate carriers and activated to various forms of
    • polyglutamate.
    • It is poorly transported across the blood–brain barrier
    • Therapeutic concentrations in the CNS occur only with high-dose therapy or by intrathecal administration
    • Used to treat or prevent leukemic meningitis. (MCQ)
    • Used in childhood acute lymphoblastic leukemia,choriocarcinoma (MCQ)
    • useful in combination with other drugs in the treatment of (MCQ)
      • Burkitt’s lymphoma and other non-Hodgkin lymphomas
      • osteogenic sarcoma, lung carcinoma,
      • head and neck carcinomas.
    • Used for (MCQ)
      • reatment of severe psoriasis
      • immunosuppression following transplantation
      • management of refractory rheumatoid arthritis, Crohn disease, Takayasu arteritis, and Wegener granulomatosis
      • for therapeutic abortion.
    • Adverse effects
      • Myelosuppressive
        • Dose monitoring and leucovorin (folinic acid) ‘‘rescue’’ are important adjuncts to successful therapy  (MCQ)
        • leucovorin is converted to an essential cofactor for thymidylate sythetase
      • produce severe GI disturbances
      • alopecia, headache, and mucositis are common. (MCQ)
      • Renal toxicity may occur because of precipitation (crystalluria) of the 7-OH metabolite of methotrexate. (MCQ)
  • Pemetrexe
    • The primary action – inhibition of thymidylate synthetase (MCQ)
    • It is approved for use with cisplatin to treat mesothelioma. (MCQ)
  • Cytarabine(ara-C)
    • It is a pyrimidine antagonist (MCQ)
    • analogue of deoxycytidine
    • inhibits the activity of DNA polymerases (MCQ)
    • most active in the S phase of the cell cycle.
    • useful for the induction of remission in  AML (MCQ)
    • used in the treatment of non-Hodgkin lymphoma.
    • highly myelosuppressive
    • cause GI disturbances.
  • Fluorouracil(5-FU)
    • a pyrimidine antagonist
    • needs to be converted to 5-fluoro-2– deoxyuridine-5-monophosphate, F-dUMP, inhibits thymidylate synthetase  (MCQ)
    • inhibits  production of dTMP and DNA
    • forms a ternary complex between itself, N5,N10- methylenetetrahydrofolate, and the enzyme.
    • administered parenterally;
    • administered topically to treat skin cancers. (MCQ)
    • major use of this agent is in the treatment of (MCQ)
      • breast and GI carcinomas
      • metastatic colon carcinomas, sometimes by infusion into the hepatic artery.
      • Applied topically,fluorouracil is used to treat premalignant keratosis and superficial basal cell carcinomas.
  • Capecitabine
    • converted to 5-FU once ingested (MCQ)
    • It is an oral agent
    • used for
      • metastatic breast cancer when patients are resistant to paclitaxel/anthracycline therapy  (MCQ)
      • metastatic colorectal cancer (MCQ)
    • Dermatitis and myelosuppresion are common with the use of this agent
    • Hepatic enzymes should be monitored, as capecitabine may elevate bilirubin levels.
  • Gemcitabine
    • pyrimidine antagonist  (MCQ)
    • inhibits DNA synthesis via chain termination.
    • an IV agent used for (MCQ)
      • pancreatic cancer
      • non–small-cell lung cancer
      • bladder cancer. 
  • 6-Mercaptopurine and 6-thioguanine
    • 6-Mercaptopurine and 6-thioguanine are purine antagonists and analogs of hypoxanthine and guanine, respectively
    • must be converted to ribonucleotides by the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to produce 6-thioguanosine-5-phosphate (6-thioGMP) and 6-thioinosine-5-phosphate (T-IMP). (MCQ)
    • 6-thio GMP can be further phosphorylated incorporated into DNA –major site of action
    • IMP accumulates and inhibits nucleotide metabolism at several steps
    • Resistance is generally due to deficiency in tumor cells of HGPRT
    • Mercaptopurine
      • administered orally.
      • incorporated into DNA and causes base mispairing. (MCQ)
      • useful in the treatment of ALL and AML (MCQ)
      • occasionally used for Crohn disease. (MCQ)
    • 6-Thioguanine
      • used for remission reduction and maintenance of AML. (MCQ)
  • Cladribine
    • a purine antagonist (MCQ)
    • an adenosine analogue (MCQ)
    • resistant to adenosine deaminase
    • It causes DNA strand breaks and loss of NAD (MCQ)
    • This agent is used for hairy cell leukemia and non-Hodgkin lymphoma. (MCQ)
    • Cladribine causes decreased CD4 and CD8 counts; how- ever, this effect is transient. (MCQ)
    • It is administered IV.
  • Fludarabine
    • a purine antagonist(MCQ)
    • interferes with DNA synthesis
    • induces cellular apoptosis.
    • used for CLL  and non-Hodgkin lymphoma. (MCQ)
    • It is an IV agent
  • Tretinoin
    • induces terminal differentiation of several precursor lines.
    • One target of tretinoin is the PML/RARa gene, which is involved in AML. (MCQ)
    • Tretinoinis used for refractory acute promyelocytic leukemia,M3 classification. (MCQ)
    • Cardiac dysrhythmias as well as dermatologic side effects are observed.
    • also commonly used for treatment of acne and wrinkles.
  • Vinca alkaloids
    • Vinca alkaloids bind to beta-tubulin hetero dimers and block polymerization with alpha-tubulin into microtubules
    • They disrupt microtubule assembly and the formation of the mitotic spindle. (MCQ)
    • These agents are most active during mitosis at metaphase (MCQ)
    • They blocking chromosomal migration and cell division. (MCQ)
    • Resistance is often accounted for by increased levels of the MDR 1 gene product P-glycoprotein that transports drugs out of the cell.
    • Vinblastine
      • administered IV.
      • bone marrow suppression with leukopenia is the dose-limiting toxicity; (MCQ)
      • used in combination with bleomycin and cisplatin for metastatic testicular tumors (the PVB regimen)
      • used for Hodgkin disease (the ABVD regimen ) (MCQ)
    • Vincristine
      • administered IV
      • it is less toxic to bone marrow than vinblastine
      • Peripheral neuropathies are the dose-limiting toxicities (MCQ)
      • used in combination with prednisone to induce remissions in childhood leukemia. (MCQ)
      • used in several important combinations
        • MOPP regimen for advanced Hodgkin disease
        • treatment of non-Hodgkin lymphoma (the CHOP regimen) (MCQ)
        • treatment of rhabdomyosarcoma, and nephroblastoma.
      • It is not cross-resistant with vinblastine.
    • Vinorelbin
      • can be given orally.
      • It has an intermediate toxicity profile relative to vinblastine and vincristine.
      • Used to treat non–small-cell lung cancer and breast and cervical cancer.
  • Taxanes:paclitaxel and docetaxel
    • Paclitaxel
      • stabilizes microtubule formation to disassembly with arrest in mitosis. (MCQ)
      • shows activity in ovarian cancer and in breast and non–small-cell lung cancer, and Kaposi sarcoma.
    • Docetaxel
      • used in androgen-refractory prostate cancer. (MCQ)
      • administered IV.
      • Resistance is associated with expression of P-glycoprotein.
      • Myelosuppression and peripheral neuropathies are the dose-limiting toxicities
      • Paclitaxel also causes hypersensitivity specific to the vehicle (50% polyethoxylated castor oil and 50% ethanol) used for its administration.
        • Co-administration of an histamine H1-receptor antagonist (e.g., diphenhydramine), a histamine H2-receptor antagonist (e.g., cimetidine), and dexamethasone reduces the incidence of hypersensitivity.
    • Epipodo phyllo toxins
      • They block cells at the boundary of the S phase (MCQ)
      • They prevent entry into the G2 phase. (MCQ)
      • These agents act by forming a ternary complex with topoisomerase II and DNA,resulting in double-stranded DNA breaks. (MCQ)
    • Etoposide,teniposide
      • Administered IV.
      • used for recalcitrant testicular tumors  (MCQ)
      • in combination with cisplatin, for small-cell lung carcinoma and AML.
      • Teniposide is used for ALL. (MCQ)
    • Antibiotics
    • Dactinomycin(actinomycin D)
      • peptide isolated from Streptomyces
      • most potent cytotoxic agents.
      • intercalates between adjacent guanosine–cytosine base pairs of the DNA double helix to form a very stable complex.
      • This agent is phase non specific. (MCQ)
      • Strongly impairs RNA synthesis and,to a lesser extent,DNA synthesis.
      • Administered by IV infusion.
      • used to treat (MCQ)
  • rhabdomyosarcoma
  • Wilms tumor in children
  • gestational trophoblastic tumor
  • metastatic testicular carcinoma
  • Ewing sarcoma.
  • used in combination with vincristine and cyclophosphamide for the treatment of solid tumors in children. (MCQ)
  • Doxorubicin (Adriamycin,), daunorubicin (daunomycin ), idarubicin , and the analogs of doxorubicin, epirubicin, valrubium , and mitoxantrone
    • DNA-intercalating agents that block the synthesis of DNA and RNA. (MCQ)
    • fragment DNA because of the (MCQ)
      • inhibition of topoisomerase II
      • generation of superoxide anion radicals.
    • Primarily toxic during the S phase of cell cycle. (MCQ)
    • administered IV.
    • produce both reversible acute and irrevers-ible chronic cardiomyopathies
    • Doxorubicin
      • It is part of the (MCQ)
        • ABVD regimen (as adriamycin) for Hodgkin disease
        • CHOP regimen (as hydroxydaunomycin) for non-Hodgkin lymphoma
        • CAF regimen (as adriamycin) for breast carcinoma
        • M-VAC regimen for bladder carcinoma
        • VAD regimen for multiple myeloma.
    • Daunorubicin and idarubicin are used
      • primarily in the treatment of acute lymphocytic and myelogenous leukemias, often in combination with cytarabine.
    • Epirubicin
      • Used for early stage,as well as metastatic,breast cancer.
    • Valrubicin
      • Used to treat refractory urinary bladder cancer
    • Mitoxantrone
      • Is used to treat prostate cancer and non-Hodgkin lymphoma.
  • Bleomycin
    • a mixture of copper-chelating glycopeptides produced by Streptomyces verticillus
    • It causes DNA chain scission and fragmentation
    • Cells with chromosomal aberrations accumulate in the G2 phase of the cell cycle. (MCQ)
    • inactivated by bleomycin hydrolase, which is found in many tissues— except skin and lung—that are major sites of toxicity.
    • administered parenterally
    • used to treat
      • testicular carcinoma
        • usually in combination with cisplatin and etoposide, or vinblastine and cisplatin, PVB regimen
      • squamous cell carcinomas.
      • also used in combination chemotherapy for Hodgkin (ABVD regimen) and non-Hodgkin lymphomas. (MCQ)
    • Adverse effects
      • most serious adverse effect is a cumulative dose-related pulmonary toxicity causes serious cutaneous toxicity. (MCQ)
  • Camptothecins
    • Topotecan
      • a natural compound derived from Camptotheca acuminata.
      • inhibits topoisomerase I resulting in DNA damage (MCQ)
      • used for ovarian cancer and small-cell lung cancer (MCQ)
      • main side effect of this drug is myelosuppression.
    • Irinotecan
      • inhibitor of topoisomerase I. (MCQ)
      • used for metastatic colorectal cancer in combination with 5-FU and leucovorin.
      • Toxicity of this drug includes
        • diarrhea, which can be severe
        • myelosuppression
  • Cisplatin
    • Cisplatin is a small platinum coordination complex
    • enters cells by diffusion and active transport
    • After intracellular replacement of its chloride atoms by water, it acts by complexing with DNA to form crosslinks. (MCQ)
    • Adjacent guanines are most frequently cross linked (MCQ)
    • leads to the inhibition of DNA replication and transcription.
    • effect is most prominent during the S phase of the cell cycle. (MCQ)
    • administered IV.
    • used to treat
      • testicular tumors  – usually with bleomycin and vinblastine, PVB regimen (MCQ)
      • ovarian carcinomas with doxorubicin (MCQ)
      • bladder carcinomas
  • Toxicity
    • cumulative damage to the renal tubules (MCQ)
      • dose-limiting toxicity of cisplatin
      • it is  irreversible following high or repeated doses
      • routinely prevented by hydration and diuresis of the patient.
    • almost always produces nausea and vomiting
    • It is ototoxic, with tinnitus and hearing loss (MCQ)
    • it also produces peripheral neuropathy (MCQ)
    • it is only moderately myelosuppressive.
  • Carboplatin
    • administered IV
    • used for patients with  (MCQ)
      • ovarian cancer
      • non-Hodgkin lymphoma
      • non–small-cell lung cancer
      • testicular cancer
      • transitional cancers of the urinary tract.
    • dose-limiting toxicity of carboplatin is myelosuppression.
  • Oxaliplatin
    • used for metastatic colon cancer (MCQ)
    • used  in conjunction with 5-FU and leucovorin.
    • cause myelosuppression and peripheral neuropathy.
  • Procarbazine
    • Needs to be activated metabolically.
    • produces chromosomal breaks
    • inhibits DNA,RNA,and protein synthesis.
    • administered orally
    • It is lipophilic and enters most cells by diffusion;
    • it is found in the CSF.
    • Therapeutic uses
      • particularly useful in the treatment of Hodgkin disease as part of the MOPP regimen (MCQ)
      • active against non-Hodgkin lymphoma and brain tumors.
    • has no cross-resistance with other anti cancer drugs. (MCQ)
    • Augments the effects of sedatives.
    • It also causes infertility. (MCQ)
    • Procarbazine is a weak monoamine oxidase inhibitor that may cause hypertension,particularly in the presence of sympathomimetic agents and food with high tyramine content. (MCQ)
    • This agent has a 10% risk of causing acute leukemia. (MCQ)
  • Hydroxyurea
    • inhibits ribonucleoside diphosphate reductase (MCQ)
    • acts during the S-phase of the cell cycle (MCQ)
    • ribonucleoside diphosphate reductase   (MCQ)
      • catalyzes the conversion of ribonucleotides to deoxyribonucleotides
      • crucial for the synthesis of DNA.
    • primarily used in the management of chronic granulocytic leukemia and other myeloproliferative disorders.
    • This agent synergizes with radiotherapy.
    • major adverse effect of hydroxyurea is hematopoietic depression.
  • L-asparaginase
    • an enzyme that reduces levels of L-asparagine
    • inhibits protein synthesis and cell division.
    • L-asparagine is an amino acid not synthesized by some tumors
    • This agent is synergistic with methotrexate when the folic acid analogue is administered prior to L-asparaginase.
    • L-asparaginase is administered IV or intramuscularly.
    • used in  (MCQ)
      • lymphoblastic leukemia
      • for the induction of remission in ALL (with vincristine and prednisone).
    • minimally marrow suppressive
    • it is toxic to the liver and pancreas
    • Hypersensitivity and anaphylactic shock to the protein may develop.
    • Hemorrhaging may occur due to the inhibition of clotting factor synthesis.
  • Bortezomib
    • inhibits proteosome signaling pathways (NF-KB) (MCQ)
    • Cancerous cell rely on proteosomes for proliferation as well as metastases.
    • approved for treatment of multiple myeloma in patients who have received at least two prior courses of therapy.
    • GI complaints are the most common side effects of bortezomib
    • peripheral neuropathy has also been reported.
  • Biologic agents
  • Cytokines and cytokine modifiers
    • Interferon alfa-2b (MCQ)
      • approved for treatment of hairy cell leukemia, and Kaposi sarcoma.
    • Interleukin-2  (MCQ)
      • approved for metastatic kidney cancer and melanoma.
    • Thalidomide and lenalidomide
      • tumor necrosis factor modifiers. (MCQ)
      • assist in degradation of THF-a mRNA encoding protein
      • used in treatment of brain tumors, Kaposi sarcoma, multiple myeloma
      • Thalidomide’s most common adverse effects
        • sedation, constipation
        • peripheral neuropathy (30%).(MCQ)
        • also highly teratogenic
      • Lenalidomide
        • analog of thalidomide
        • increased potency and an apparent decreased toxicity.
  • Tyrosine kinase inhibitors
  • Imatinib ,Dasatinib
    • tyrosine kinase inhibitors that are specific for Bcr-Abl onco- protein (MCQ)
    • used for chronic myelogenous leukemia (MCQ)
    • Imatinib has also been used for GI stromal tumors (GIST) (MCQ)
    • GISTs express another tyro- sine kinase inhibited by Imatinib, c-kit (MCQ)
    • Dasatinib is also used for ALL. (MCQ)
  • EDGF Receptor tyrosine kinase inhibitors
  • Gefitinib
    • An inhibitor of epidermal growth factor receptor tyrosine kinase. (MCQ)
    • It is approved for use in non–small-cell lung cancer where it is generally used with gemcitabine and cisplatin.
  • Erlotinib
    • Inhibitor of epidermal growth factor receptor tyrosine kinase. (MCQ)
    • used for
      • non–small-cell lung cancer in patients who have failed at least
      • one trial of prior chemotherapy
      • advanced pancreatic cancer.
  • Monoclonal antibodies (MABs)
  • Rituximab
    • a chimeric (human/mouse) antibody to IgG  (MCQ)
    • binds to CD20 antigen on B cells.  (MCQ)
    • This antigen is overexpressed on B cells of non-Hodgkin lymphoma tissues. (MCQ)
    • net effect of this interaction is cell lysis secondary to antibody-dependent cy- totoxicity or complement cytotoxicity. (MCQ)
    • used for relapsed non-Hodgkin lymphoma (R-CHOP regimen). (MCQ)
    • It is also used for mantle cell lymphoma. (MCQ)
  • Trastuzumab
    • a humanized IgG antibody (MCQ)
    • against the epidermal growth factor receptor, HER2/neu(MCQ)
    • HER2/neu is overexpressed in 25%–30% of breast cancers. (MCQ)
      • Expression of this protein is associated with decreased survival due to more aggressive disease
    • The net effect is the arrest of the cell cycle via antibody-mediated cytotoxicity.
    • This agent is used in HER2/neu-positive metastatic breast cancers in combination with paclitaxel.
  • Cetuximab
    • a chimeric human–mouse IgG antibody to epidermal growth factor recep- tor (EGFR). (MCQ)
    • Its mechanism of action differs from that of imatinib in that cetuximab actually blocks the receptor.
    • The action of this drug results in inhibition of cancer cell growth and induction of apoptosis (MCQ)
    • Overexpression of EGFR in colorectal cancer is associated with decreased survival and overall poor prognosis.
    • cetuximab  is currently approved for EGFR-expressing metastatic colon cancer alone or in combination with irinotecan. (MCQ)
  • Bevacizumab
    • first humanized IgG directed against human vascular endothelial growth factor (VEGF) interaction with its receptors (VEGFR1, VEGFR2), which are involved in angiogenesis, an important process in cancer proliferation and metastasis. (MCQ)
    • Approved for meta static colon cancer in combination with 5-FU.
    • Cause  rarely bowel perforation.
  • Steroid hormone agonists and antagonists and related drugs
  • Adreno corticosteroids
    • prednisone,hydroxycortisone,dexamethasone
    • Lymphocytic and anti mitotic agents. (MCQ)
    • can be administered orally.
    • useful in
      • acute leukemia in children
      •  malignant lymphoma
      • both Hodgkin and non-Hodgkin lymphoma (CHOP and MOPP regimens). . (MCQ)
  • Mitotane
    • an oral agent specific for the treatment of inoperable adrenocortical carcinoma. . (MCQ)
    • inhibits glucocorticoid biosynthesis . (MCQ)
    • selectively causes atrophy of the tumors within zona reticularis and fasciulata
    • CNS depression is the dose-limiting toxicity.
  • Progestins
    • useful in the management of endometrial hyperplasia and carcinoma . (MCQ)
    • second-line therapy for metastatic hormone-dependent breast cancer
    • Megestrol
      • useful to stimulate appetite in patients with cancer and AIDS-related cachexia. . (MCQ)
  • Estrogens
    • inhibit the effects of endogenous androgens and androgen-dependent metastatic prostatic carcinoma. (MCQ)
    • used for palliative purposes in metastatic breast cancer
    • Diethylstilbestrol is usually the agent of choice. . (MCQ)
    • more effective when combined with orchiectomy.
    • Adverse effects
      • Cardiac and cerebrovascular complications
      • carcinoma of breast, endometrium, and ovary
  • SERMS: Tamoxifen  , Toremifene , Raloxifen
    • SERMS (selective estrogen receptor modulators)
      • drugs that have estrogen receptor agonist or antagonist properties depending on the target tissue. (MCQ)
    • In the breast, they are estrogen antagonists.
    • inhibit estrogen-dependent cellular proliferation (MCQ)
    • increase the production of the growth inhibitor TGF-b (transforming growth factor-beta) (MCQ)
    • administered orally
    • reach steady-state in 4–6 weeks.
    • Tamoxifen and toremifene
      • used in postmenopausal women with or recovering from meta- static breast cancer. (MCQ)
      • effective in patients who have estrogen receptor–positive tumors (MCQ)
      • They have no effect in ER-negative tumors(MCQ)
      • Recommended treatment duration is 5 years.
      • Used in premenopausal women with estrogen receptor-positive tumors.
      • Tamoxifen is used as adjunctive therapy to oophorectomy and to leuprolide or goserelin
      • Tamoxifen and raloxifen are used as prophylactic agents in women at high risk for breast cancer. (MCQ)
      • adverse effects of tamoxifen
        • Moderate nausea, vomiting, and hot flashes
        • endometrial cancer and thrombosis on long-term therapy.
  • Pure anti estrogens, Fulvestrant (MCQ)
    • it has no agonist activity in any tissue.
    • pproved for use in hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy
  • Gonadotropin-releasing hormone analogues: leuprolide , triptorelin and goserelin
    • peptides
    • on long-term administration, inhibit LH and FSH  secretion from the pituitary (MCQ)
    • reduce the circulating levels of gonadotropins
    • reduce estrogen and testosterone
    • Use of these agents results in castration levels of testosterone in men and postmenopausal levels of estrogen in women.
    • effective in prostatic carcinoma and in estrogen-positive breast cancer. (MCQ)
    • Why Leuprolide and goserelin are combined with antiandrogen flutamide or bicalutamide ? (MCQ)
  • Initial administration before pituitary-receptor desensitization occurs, may result in increased LH and FSH release, with a transitory increase in testosterone and an exacerbation of disease.
  • Leuprolide and goserelin are often administered with antiandrogen flutamide or bicalutamide , which block the translocation of androgen receptors to the nucleus and thereby prevent testosterone action.
  • Aromatase inhibitors: Anastrozole , Letrozole , Exemestane , Amino-glutethimide
    • Recommendation : every postmenopausal woman with ER-positive breast cancer receive adjuvant aromatase inhibitor therapy. (MCQ)
    • Anastrozole and letrozole
      • reversible aromatase inhibitors (MCQ)
      • have no effect on synthesis of steroids other than estrogens
      • Uses
        • adjunct for postmenopausal women with ER-positive early breast cancer, women with breast cancer who have progressed on tamoxifen(MCQ)
        • first-line treatment of ER-positive or ER-unknown advanced local breast cancer. (MCQ)
      • Anastrozole offers advantage over Tamoxifen
        • Anastrazole is approved for use in women who have received 2–3 years of tamoxifen and are switching to anastrazole for a total of 5 years of adjunct therapy.
      • An adverse effect of these drugs is hot flashes and vasomotor symptoms.
      • Long-term effects include osteopenia and osteoporosis(MCQ)
      • Alendronate is a useful adjunct for both drugs.
    • Exemestane
      • inhibits aromatase irreversibly. (MCQ)
      • used for postmenopausal women with breast cancer who have progressed on tamoxifen.
      • approved for up to 5 years of use for women switching from tamoxifen
      • does not exhibit cross-resistance with other aromatase inhibitors. (MCQ)
      • Side-effect profile includes hot flashes and fatigue.
    • Aminoglutethimide
      • inhibits corticosteroid synthesis (MCQ)
      • also inhibits enzyme aromatase, which aids in conversion of androstenedione to estrone. (MCQ)
      • This agent is used in treatment of
        • metastatic receptor-positive breast cancer (both estrogen and progestin receptors)
        • prostate cancer. (MCQ)
      • Hydrocortisone has to be administered at the same time to prevent adrenal insufficiency.
      • This agent is oral
      • its lack of specificity has reduced its overall use.
  • Androgen antagonists :flutamide  , bicalutamide ,nilutamide
    • Flutamide and bicalutamide
      • competitive antagonists of the androgen receptor(MCQ)
    • nilutamide
      • an irreversible inhibitor of the androgen receptor. (MCQ)
      • used in combination with either chemical or surgical castration for the treat- ment of prostate cancer.
    • Adverse effects are due to decreased androgen activity
      • fatigue, loss of libido, and impotence
      • decreased hepatic function and GI disturbances.
  • ADJUNCT AGENTS
  • Leucovorin (folinic acid)
    • is a form of folate that is used to ‘rescue’’ patients from(MCQ)
    • methotrexate toxicity
    • combination regimens with 5-FU.
  • Filgrastim  and pegfilgastim
    • are recombinant human G-CSF agents (MCQ)
    • increase neutrophil production
    • used for prophylaxis and treatment of chemotherapy-induced neutropenia.
  • Sargramostim
    • a recombinant GM-CSF (MCQ)
    • used to assist graft recovery in patients undergoing bone marrow transplantation.
  • Epoetin alfa (Epogen) and darbepoetin alfa
    • analogs of erythropoietin.
    • used in anemia caused by chemotherapy or renal failure
  • Allopurinol
    • A purine analog
    • used during chemotherapy to prevent acute tumor cell lysis that results in severe hyperurice- mia and nephrotoxicity. (MCQ)
  • Oprelvekin
    • a recombinant interleukin (MCQ)
    • indicated for
      • chemotherapy- induced thrombocytopenia (MCQ)
      • prophylaxis of this potentially dangerous complication.
  • Amifostine
    • a cytoprotective agent (MCQ)
    • dephosphorylated to active free thiol
    • acts as a scavenger of free radicals.
    • It is used to reduce renal toxicity associated with cisplatin therapy(MCQ)
    • also used to reduce xerostoma in patients undergoing irradiation of head and neck regions. (MCQ)

How Antineoplastic Work

Antimetabolites In Chemotherapy

Antineoplastic Agents – Part 1

Antineoplastic Agents – Part 2

What is the molecular target for the vinca alkaloids used as anticancer agents?