Anticancer Drugs General Pharmacology M212 Dr. Laila M. Matalqah Ph.D. Pharmacology

Anticancer Drugs.  Antineoplastic Drugs = Cytotoxic Drugs = Cancer chemotherapy.  Cancer cells * Uncontrolled proliferation. *Dedifferentiation & loss of function. *Invasiveness. *Metastasis.  Anticancer drugs available do not specifically recognize neoplastic cells but, rather, affect all kinds of proliferating cells, both normal and abnormal  Ideal anti cancer drug–currently not available

Main Approaches to Treat Cancer Surgical excision Radiation Chemotherapy: i – When the tumor is disseminated and not amenable to surgery TT. ii – Or as a supplement to surgery and irradiation to reduce the number of micrometastasis “adjuvant TT” iii – Before surgery to shrink the tumor “neoadjuvant TT”. iv – In lower doses to assist in prolonging a remission “maintenance TT”

Aims of Chemotherapy 1. Curative: to obtain complete remission as in Hodgkin’s disease. 2.Palliative: to alleviate symptoms and avoidance of life-threatening toxicity but with little expectation of complete remission as in esophagus Ca-dysphagia. 3.Adjuvant: Chemotherapy is also used as a supplemental treatment to attack micrometastases following surgery and radiation treatment

General ADRs of Anticancer Drugs Most of them have a narrow Therapeutic Index. 1.Nausea & vomiting: common, severe, prolonged  TT rejection. Antiemetics are needed. 2.Bone Marrow depression pancytopenia and immunosupression (antibody and cell mediated)  infection “apportunistic” – important dose limiting factor. Repeated blood count is essential. blood transfusions may be needed.

ADRs (cont.) 3.Damage to GIT lining & other mucosal surfaces  diarrhea, stomatitis and mouth ulcer. 4.Hair bulb damage: alopecia – Reversible in 2-6 months. 5.Delayed wound healing. 6.Effect on germ cells  sterility, teratogenicity and mutagenicity.

ADRs (cont.) 7.Various organ damage – renal, hepatic, cardiac,pulmonary…… 8.Secondary cancer,10 ys or more, - mutagenic effect. 9.Hyperuricemia : cell break down  purine-  uric acid  gout and renal damage 10.Local toxicity due to extravasation

Problems associated with chemotherapy 1. Resistance Inherent resistance – melanoma Acquired resistance – after prolonged (suboptimal doses) low doses. Resistance could be minimized by:  Short term, intensive, intermittent therapy, with drug combination 2. Toxicity: affects normal cells undergoing rapid proliferation (for example, cells of the buccal mucosa, bone marrow, GI mucosa, and hair follicles

Combinations of drugs Cytotoxic agents with different toxicities, and with different molecular sites and mechanisms of action, are usually combined at full doses. This results in higher response rates, due to additive cytotoxic effects and nonoverlapping host toxicities.  Advantages of drug combinations 1.Maximum cell kill & tolerated toxicity. 2.Effective against wide range of cell lines. 3.Slow or prevent development of resistance

Guidelines when selecting Drug combination 1.Use drugs that show activity against the type of tumor being treated. 2.Use drugs that have minimal or no overlapping toxicities, ADRs of the drugs should be diverse and not centered on the same organ system. 3.The dosing schedule for each drug should be optimal and doses should be given at constant times.

Guidelines when selecting Drug combination(cont.) 4. Use drug combination that result in synergistic activity  optimizing therapeutic benefits and reducing ADRs. 5. use drugs that have different mechanisms of action,or that affect tumor cells at different stages of the cell cycle.

Tumor growth rate Initially rapid, decreases as tumor size increases (?) because of unavailability of nutrients and oxygen, due to less blood supply. Radiation and surgery decrease the size  adequate blood supply  increase growth rate  increased susceptibility to chemotherapy.

Pharmacological guidelines  e.g. leukemic cells in CNS may be unaminable for some cytotoxic drugs (?) can not cross BBB  This problem will be solved by Intrathecal administration and or irradiation of cranio- spinal axis.  Similarly, drugs may be unable to penetrate certain solid tumors.!!!

Classification of Anticancer Drugs 1. Antimetabolites. 2. Alkylating agents. 3. Antibiotics. 4. Mytotic spindle poisons. 5. Hormones. 6. Monoclonal antibodies

Antimetabolites Are structurally related to normal cell components. They interfere with the availability of purine or pyrimidine nucleotide precursors. By :1. inhibiting their synthesis or 2. competing with them on DNA & RNA synthesis

Antimetabolites Methotrexate (MXT) “Antifolate”, inhibits Dihydrofolate reductase (DHF) enzyme, decreasing tetrahydrofolate (THF) production  DNA&RNA The inhibition of DHFR can only be reversed by administration of leucovorin or folinic acid rescue (FH4). USES: acute lymphocytic leukemia (ALL), breast cancer, choriocarcinoma,, and head and neck Carcinomas, Severe psoriasis & rheumatoid arthritis.

Antimetabolites Methotrexate (MXT) ADRs: Pulmonary toxicity Renal damage: high-dose MTX and its 7-OH metabolite, which can precipitate in the tubules. –Alkalinization of the urine and hydration help to prevent this problem Common: stomatitis, myelosuppression, erythema, rash, urticaria, and alopecia. Some of these adverse effects can be prevented or reversed by administering leucovorin

Other Antimetabolites (AM) 6-Mercaptopurine (purine AM). Uses: Acute leukemias, ADR: Hepatotoxicity Cytoarabine (pyrimidine AM). In: Acute leukemias. 5- Flurouracil - (pyrimidine analogue, inhibits thymidylate synthetase – inhibit DNA synthesis). Uses: breast cancer, Ovary, skin & GIT carcinoma

Alkylating Agents MOA: by covalently binding to nucleophilic groups on various cell constituents - Transferring an alkyl group to DNA in the N-7 of guanine  breakage of DNA strand and cross linkage of two strands at two guanines  blockade of DNA synthesis and tumor cell death.

Alkylating Agents Cyclophosphamide Inactive, metabolized by hepatic P-450 to: Phosphoramide (active cytotoxic) and Acrolein (haemorrhagic cystitis) administered by the oral route Used in: Lymphomas, Lymphocytic Leukemia, breast &ovary Ca Haemorrhagic cystitis is minimized by:  high fluid intake  Irrigation of the bladder with N-acetylcysteine  Adequate hydration as well as IV injection of MESNA (sodium 2-mercaptoethane sulfonate), which neutralizes the toxic metabolites (acrolein)

Other Alkylating Agents Nitrosoureas :Carmustine (IV) & Lomustine (Orally) Cross BBB  in tumor of brain and meninges. Busulfan: selective on BM Uses In: mylogenic leukemia ADRs : pulmonary fibrosis

Other Alkylating Agents Cisplatin: MOA: similar to alkylating agent. In: Ca testes, bladder, lung and ovary. ADRs: Ototoxicity, hepatoxicity,nephrotoxicity and neurotoxicity

Cytotoxic Antibiotics Produce their effects mainly by direct action on DNA 1.Doxorubicin and daunorubicin : MOA: Free radical generator  inhibit NA synthesis. In : Leukemias and lymphomas and other solid tumors. ADRs: dose-dependent Cardiotoxicity –arrhythmias &CHF 2.Bleomycin: Free radical generator. Uses: squamous cell Carcinoma, lymphoma ADRs: Pulmonary toxicity (Pulmonary fibrosis and pneumonia)

Mitotic Spindle Poisons Vincristine (VX) and Vinblastine (VBL) From vinca alkaloids MOA: Microtubule inhibitors- Inhibits mitosis at metaphase by binding to tubulin (M-phase). Uses: Acute leukemias, lymphomas, and sarcomas ADRs: Local tissue damage, Thrombophlebitis and NM effects as muscle weakness and parasthesia.

Hormones and Hormone antagonists 1. prednisone reduced to Prednisolone. Used in lymphomas and leukemias. 2. Estrogens in prostate Ca, Ca breast in the male. 3. Antiestrogen “Tamoxifen” in Ca breast in female. (estrogen receptor antagonist) 4. Progestogens in endometrial tumors and Ca breast and prostate. 5. Androgens in Ca breast.

Monoclonal Antibodies Rituximab and Cetuximab MOA: binds to cytotoxic B lymphocytes, inducing complement and antibody dependent, cell- mediated cytotoxicity of the B cells. It is important to infuse rituximab slowly : can cause Hypotension, bronchospasm, and angioedema Pretreatment with diphenhydramine, acetaminophen, and bronchodilators Uses: chronic lymphocytic leukemia.