ANTICANCER DRUGS & IMMUNOMODULATORS

“CANCER” Refers to a Malignant neoplasm (New growth) Cancer cells can manifest: Uncontrolled Proliferation. Loss of function due to lack of ability to differentiate. Invasiveness. The ability to metastasize.

Cancer arises as a result of a series of genetic changes as well as life style in the cell, the main genetic lesions being: Inactivation of tumor suppressor genes. The activation of oncogenes.

TREATING CANCER Treatment methods Surgery Radiation Chemotherapy (drugs) Different cancers respond to different treatments.

Antineoplastic drugs Are cytotoxic not tumoricidal Only kill cells during mitosis, and Not all cancer cells are dividing at the same time. SUCCESS DEPENDS ON: Stage of cancer at time of diagnosis Type of cancer Development of drug resistance Overall health of patient.

Problems with Chemotherapy Toxicity to normal cells Dose limiting We don’t have cancer specific drugs High growth fraction human cells affected Bone marrow GIT epithelium Hair follicles

Problems with Chemotherapy Goal of treatment is a “CURE” REQUIRES 100% KILL RATE Solid tumors respond poorly Drug resistance Heterogeneity of cancer cells Limited drug access to tumor cells

THERAPEUTIC STRATEGIES COMBINATION THERAPY Attack diff. mechanisms Different molecular sites Different toxicities Suppress drug resistance OPTIMIZING DOSAGE SCHEDULES REGIONAL DRUG DELIVERY Intrathecal, IV etc.

Log kill Chemotherapeutic agents follow first order kinetics A given dose of a drug destroys a constant fraction of cells. 10 to power of nine leukemic cells present and treatment gives 99.999 percent kill, then o.oo1 percent of 10 to power of 9 cells would remain ie10 power of 4. This gives a five-log kill. At this point, the patient appears asymptomatic (in remission) and additional treatment is required to totally eradicate the leukemic cell population.

Benefits of chemotherapy CURE PALLIATION PROLONGATION OF USEFUL LIFE

CELL GROWTH CYCLE 5 DISTINCT PHASES OF MITOSIS 1. G0 - Resting - no mitosis 2. G1 - Post mitotic - first growth 3. S - DNA synthesis phase (replication) 4. G2 - Premitotic - second growth 5. M - Mitosis phase (cell divides) GENERATION TIME - one complete cycle different in all tumors, from hours to days

M G2 M PHASE S G1 G0 Synthesis R Premitotic Interval SPECIFIC MITOSIS vincristine vinblastine paclitaxel PROPHASE METAPHASE ANAPHASE TELOPHASE S PHASE SPECIFIC Cytosine Arbinoside Hydroxyurea SELF LIMITING 6-Mercaptpurine Methotrexate. S DNA Synthesis MITOSIS PHASE NONSPECIFIC alkylating agents, cis -platinum nitrosoureas, dacarbazine antibiotics procarbazine Tumor Suppressor Genes -ve (p53) Growth Factors Oncogenes +ve G1 G0 G0 R Differentiation

PENTOSTATIN PALA Purine HYDROXYUREA DNA Pyrimidine synthesis synthesis Inhibits Pyrimidine Biosynthesis Inhibits adenosine Deaminase Ribonucleotides 6-MERCAPTOPURINE 6-THIOGAUNINE HYDROXYUREA Inhibit Ribonucleotide Reductase Inhibit Purine ring biosynthesis Deoxyribonucleotides Inhibit Nucleotide interconversions METHOTREXATE 5-FLOUROURACIL Inhibit dihydrofolate reduction, blocks TMP and Purine synthesis Inhibit TMP Synthesis DNA

Inhibit DNA, RNA synthesis BLEOMYCIN ETOPOSIDE CYTARABINE FLUDARABINE 2-CHLORODEOXY ADENOSINE DNA Damage DNA and Prevent repair Inhibit DNA Synthesis DACTINOMYCINE DAUNORUBICIN DOXORUBICIN MITOXANTRONE ALKYLATING AGENTS MITOMYCETIN CISPLATIN PROCARBAZINE DACARBAZINE Intercalate with DNA Inhibit DNA, RNA synthesis RNA (Transfer, messenger, ribosomal) Form adducts w/ DNA A-ASPARAGINASE PACLITAXEL VINCA ALKALOIDS NAVELBINE Deaminate asparagine PROTEINS Inhibits protein synthesis Inhibit function of Microtubules Enzymes Microtubules

ANTINEOPLASTIC DRUGS ADVERSE EFFECTS: cytotoxic to all fast growing cells Hair follicles GI tract mucosa Bone marrow suppression (BMS) causing anemia and leukopenia All are CI in pregnancy Most are nephro - hepato- and ototoxic Extravasation of IV can result in loss of limb

Antineoplastic Agents ADVERSE EFFECTS: (Contd) All have a BMS and emetic index All have wide interaction with other drugs. Special training required for nursing

Treatment of bone marrow suppression Neutropenia: filgastrim Thrombocytopenia: platelet transfusion Anemia: erythropoietin, packed red blood cell transfusion

DEFINITIONS: % of cells in mitosis at any given time GROWTH FRACTION % of cells in mitosis at any given time LEUCOVORIN RESCUE - use of leucovorin to reverse methotrexate-induced toxicity MITOTIC INDEX number of cells per unit undergoing mitosis during a given time

ANTINEOPLASTIC AGENTS 2 MAIN GROUPS OF AGENTS: CELL CYCLE - NONSPECIFIC (CCNS) ALKYLATING AGENTS cytotoxic in any phase of cell cycle effective against slowly growing tumors & fast growing tumors CYTOTOXIC ANTIBIOTICS (some are CCNS) CELL CYCLE - SPECIFIC (CCS) ANTIMETABOLITES - cytotoxic in S phase MITOTIC INHIBITORS - cytotoxic in M phase effective against rapidly growing tumors

Alkylating Agents Carmustine Lomustine Cyclophosphamide Ifosfamide Mechlorethamine Streptozotocin Mitomycetin Dacarbazine Chlorambucil

mechlorethamine MOA: ALKYLATES THE N7 nitrogen of a guanine residue in one or both strands of DNA molecule. It leads to: Cross linkage of guanine residues in the DNA chains thus facilitating strand break

ALKYLATING AGENTS NITROGEN MUSTARDS CCNS killing ability Mechlorethamine is the prototypical agent USES: Hodgkin’s disease & lymphomas. leukemias, CANCERS OF solid tumors lung, breast, ovary, testes, brain, bladder,

ALKYLATING AGENTS SELECTED AGENTS: Mechlorethamine IV only (adult use only) Carmustine IV, adult only, can cross blood-brain barrier, therefore used to treat brain lesions

Cyclophosphamide IV and PO, adults and pediatric use USES: burkitt lymphoma, breast cancer, Other uses: nephrotic syndrome, intractable rheumatoid arthritis SE: BMS esp leukocytosis, hemorrhagic cystitis which can lead to fibrosis of the bladder(due to acrolein), alopecia, nausea, diarrhea

Cyclophosphamide (Inactive) Hepatic Cytochrome P450 0xidase Aldophosphamide 4-Hydroxycyclophosphamide Hepatic aldehyde oxidase Enzymatic Non enzymatic 4-Ketocyclophosphamide (Inactive). Acrolein Cytotoxic Phosphoramide Mustard Cytotoxic Carboxyphosphamide (Inactive). Responsible for unwanted effects

Melphalan Chlorambucil Busulfan USES: Melphalan: multiple myeloma Chlorambucil : chronic lymphocytic leukemia Busulfan: chronic granulocytic leukemia SE: Myelosuppression

Antimetabolites Cytarabine Fludarabine 5-Fluorouracil 6-Mercaptopurine Methotrexate 6-Thioguanine Pentostatin 2-Chlorodeoxy Adenosine Capecitabine Gemcitabine

ANTIMETABOLITES Antagonism of folate (Methotrexate) ACTIONS: Antagonism of folate (Methotrexate) Antagonism to Purines, and Pyrimidines needed for synthesis of nucleic acids - Stops cell replication

USES: Solid tumors (breast, lung, liver, brain, colon. Stomach, pancreas) Lymphomas, leukemias. Some agents also immunosuppressive, Useful in treating immune-mediated diseases

ANTIMETABOLITES PO & IM, adult and pediatric use SELECTED AGENTS: (FOLIC ACID ANALOG) METHOTREXATE Folic acid antagonist PO & IM, adult and pediatric use Also used to treat immune-mediated diseases, Used in combination with Misoprostol for therapeutic abortion Causes profound anemia (folate depletion) Therefore leucovorin “rescue” often used to counteract

ANTIMETABOLITES PYRIMIDINE CYTOSINE ANALOG - SELECTED AGENTS: CYTARABINE -Pyrimidine antagonist -IV and intrathecal (within spinal canal) SE: VOMITING, MYELOSUPPRESSION

Antimetabolites SELECTED AGENTS: PURINE, HYPOXATHINE ANALOG 6- MERCAPTOPURINE (6-MP) - Purine antagonist - PO only, adult and pediatric use USES: remission of ALL, crohn disease Drug interaction btw 6-MP and allopurinol( therefore dose of 6-Mp have to be decreased in these patients to avoid its accum

5 fluorouracil Pyrimidine analog Interferes with conversion of deoxyuridylic acid to thymidylic acid (thymineless death) Severe gi toxicity Dermopathy— erythematous desquamation of palms and soles --hand foot syndrome

Mitotic Inhibitors Also called Microtubule inhibitors Vincristine Vinblastine Paclitaxel Navelbine

MITOTIC INHIBITORS ACTIONS: Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) Bind to and disrupt mitotic spindles USES: Lymphomas (Hodgkin’s and non-Hodgkin’s), Neuroblastoma Kaposi’s sarcoma, Solid tumors (breast, testicular, etc.)

MITOTIC INHIBITORS PACLITAZEL SELECTED AGENTS: PACLITAZEL MOA: Hyperstabilize polymerized microtubule so that mitotic spindle cannot break down(no anaphase) IV only, adult use only Good drug for ovary and breast ca SE: myelosuppression and hypersensitivity

VINCRISTINE AND VINBLASTINE IV only, adult and pediatric use USES: WILMS’ TUMOR, CHORIOCARCINOMA, HODGKIN’S LYMPHOMA MOA: Bind to tubulin and block polymerization of microtubules so that mitotic spindle do not form

Vinblastine – potent myelosuppressant Adverse effects Severe vesicant Must be careful of IV equipment to avoid slough Vinblastine – potent myelosuppressant Vincristine - Neurotoxicity (peripheral neuritis) sensory neuropathy Severe paresthesias, loss of reflexes, ataxia, and muscle wasting

MOPP REGIMEN M—Mechlorethamine O---Oncovin (vincristne) P---Purinethol P---Procarbazine Mainly in the treatment of lymphomas

POMP REGIMEN P- prednisone O- oncovin(vincristine) M- methotrexate P- purinethol (mercaptopurine) Used in the treatment of acute lymphocytic leukemias

Antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Idarubicin Plicamycin Mitoxantrone

CYTOTOXIC ANTIBIOTICS ACTIONS: Source: Streptomyces mold - work by intercalation (insertion of drug molecule between the 2 DNA strands leading to disruption of DNA function Kill some bacteria and viruses but are too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, mostly used in combination with other agents

DACTINOMYCIN FIRST ANTIBIOTIC TO BE USED FOR CHEMOTHERAPY USED IN COMBINATION WITH VINCRISTINE FOR WILMS TUMOR WITH MTX FOR CHORIOCARCINOMA MOA; intercalates in the minor groove forming a stable dactinomycin-DNA complex which will inhibit DNA DEPENDANT RNA POLYMERASE function → inhibition of DNA synthesis Also inhibits the ligase function of topoisomerase-II → strand break→DNA syn SE: BONE MARROW DEPRESSION , IMMUNOSUPPRESSION.

CYTOTOXIC ANTIBIOTICS SELECTED AGENTS: DOXORUBICIN IV only, adult use only BLEOMYCIN IM, IV, SC, adult use only very toxic agents !!!

DOXORUBICIN & DAUNORUBICIN ANTHRACYLCLINE ANTIBIOTICS DOXORUBICIN IS HYDROXYLATED ANALOG OF DAUNORUBICIN SARCOMA, CARCINOMA OF LUNG, BREAST, ACUTE LEUKEMIAS MOA: Intercalates with DNA, generaation of free radical →inhibition of DNA synthesis SE: CARDIOTOXIC, alopecia, skin pigmentation, bone marrow suppression, GIT disturbance

BLEOMYCIN MIXTURE OF DIFFERENT COPPER CHELATED GLYCOPEPTIDES CELL CYCLE SPECIFIC.CELLS ACUMULATE IN THE G2 PHASE MOA: complexes with Fe and oxygen forming free radicals that results in DNA strand break TESTICULAR TUMORS WITH VINBLASTINE AND CISPLATIN 100% RESPONSE RATE SE: PULMONARY TOXICITY

Others Asparaginase Cisplatin Carboplatin Etoposide Hydroxyurea Interferons Procarbazine Altretamine (Hexalen) Topotecan Trastuzumab Rituximab

MISCELLANEOUS ANTINEOPLASTICS Various actions, Both CCNS and CCS Used in combinations with other agents SELECTED AGENTS: Cisplatin –Platinum coordination complex. nephrotoxic , ototoxic IV, adult and pediatric use ALTRETAMINE (Hexalen) PO only, adult use only, primarily used to treat ovarian cancer ASPARAGINASE – hydrolyzes asparagine needed for growth of cancer cell IV only, adult and pediatric use HYDROXYUREA PO only, adult use only

Steroid hormones and their antagonists Tumors which are steroid hormone –sensitive may be either Hormone responsive Hormone dependant Both Goal of treatment: hormone treatment of responsive tumors usually is only palliative

Steroid Hormones & Antagonists Adrenocortical Suppressant: Mitotane, Aminoglutethimide. 2.Adrenocortical Steroids - Prednisone 3.Progestins: Hydroxyprogesterone Medroprogestrone, Megesterol acetate.

4.Estrogens: DES, Ethinylesterdiol 5.Antiestrogens: Tamoxifen & Raloxifene 6.Antiandrogens: Flutamide 7.Gonadotropin Releasing Hormone Analog: Leuprolide

Prednisone Potent anti-inflammatory corticosteroid with less mineralocoticoid activity than cortisol Used to induce remissions in acute lymphocytic leukemia and in treatment of both hodgkins and nonhodgkins lymphoma. Adv effects- cataracts, glaucoma, hyperglycemia, osteoporosis, mood swings

Tamoxifen SERM Estrogen antagonist First line therapy for estrogen receptor positive breast cancer Binds to estrogen receptors Leading to Depletion of estrogen receptors Not related to any specific cell phase. SE: hot flashes, nausea, vaginal bleeding, discharge, thromboembolism, vision problems,

Leuprolide and goserilin Analogs of gnrh. As gnrh agonists they occupy gnrh receptor in the pituitary which leads to its desensitization and consequently inhibition of release of fsh and LH. response to leuprolide in prostatic carcinoma is equivalent to orchiectomy. Sustained release preparation, subcutaneous depot intramuscular injection.

Aromatase inhibitors Aromatase is responsible for extra-adrenal synthesis of estrogen from androstenedione which takes place in liver, fat, muscle, skin and breast tissue including breast malignancies. SE: osteoporosis

Aminoglutethimide: metastatic breast cancer in postmenopausal women Anastrozole and letrozole: estrogen dependent breast cancer Exemestane

Monoclonal antibodies Directed against specific targets Created from b lymphocytes (from immunized mice) fused with b lymphocyte tumor cells Resulting hybrid cells can be individually cloned and each clone will produce antibodies directed against a single antigen type. Recombinant tech can be used to create humanized antibodies.

Trastuzumab Rituximab Bevacizumab cetuximab

Trastuzumab In patients with metastatic breast cancer over expression of trans membrane epidermal growth factor receptor protein—HER 2 is present Usually given with paclitaxel can cause regression of cancer and metastases. MOA: works by down regulation of HER2-receptor expression , via induction of antibody-dependent cytotoxicity, decrease in angiogenesis SE: Congestive heart failure esp when given with anthracycline

Rituximab First monoclonal antibody to be approved for the treatment of cancer. Directed against cd20 antigen on the surface of normal and malignant B lymphocytes CD20 plays a role in the activation process for cell-cycle initiation and differentiation Use– post transplant lymphoma and in CLL, rheumatoid arthritis Must be infused slowly due to occurrence of fatal adverse reactions SE: hypotension, bronchospasm and angioedema, chills and fever due to activation of complement which release ILs and TNF-α Activation of TNF can result in reactivation of latent TB.

IMATINIB: MOA: acts a signal transduction inhibitor used specifically to inhibit tumor tyrosine kinase which associated with BCR-ABL fusion protein present in CML USES: Treatment of CML, GI stromal tumors SE: fluid retention

IMMUNOSUPPRESSIVE DRUGS

Overview Immune system protects the body against harmful foreign molecules. However, in some instances, this good can result in serious problems e.g., in transplantation causing rejection Transplantation of organs and tissues has become routine due to improved surgical techniques and better tissue typing.

Drugs available Drugs now available more selectively inhibit rejection of transplanted tissues while preventing the patient from becoming immunologically compromised. Earlier drugs cause patients to frequently succumb to infections due to suppression of antibody and cell-mediated immunity. Today’s approach alters lymphocyte function using drugs or antibodies against immune proteins(antigen).

Strategies of treatment Agents that interfere with cytokine production or action e.g., ILs, TNF, IFN Some disrupts cell metabolism, preventing lymphocyte proliferation Mono-and-polyclonal antibodies block T-cell surface molecules e.g., cluster of differentiation cells (CD-cells)

Selective inhibitors of cytokine production and function Cytokines are soluble, antigen-nonspecific, signaling proteins that bind to cell surface receptors on a variety of cells Cytokines include interleukins, interferons, tumor necrosis factors , transforming growth factors, colony stimulating factors. Example: IL2 stimulates proliferation of antigen primed Tcells.

Cyclosporine Cyclic peptide composed of 11 amino acids Extracted from a soil fungus

MOA: diffuses into the T-cell, binds to a cyclophilin to form a complex that inhibits calcineurin→ ultimate inhibition of synthesis and release of cytokines including IL-2→ decrease number of T-lymphocytes → cell mediated immunity Preferentially suppresses cell mediated response, humoral immunity affected less.

USES: to prevent rejection of kidney, liver and cardiac transplants . Alternative to methotrexate in treatment of rheumatoid arthritis, recalcitrant psoriasis Can be given orally or iv. Better to combine with glucocorticoid Excreted through the bile/ urine SE: Nephrotoxic, hepatotoxicity, glucose intolerance, hirsutism, gum hyperplasia

Tacrolimus (FK506) Macrolide isolated from soil fungus USES: Prevention of liver/renal transplants Given with a glucocorticoid Preferred over cyclosporine cos of its potency, decreased episode of rejection and it requires lower doses of glucocorticoid→decrease in likelihood of steroid associated adverse effect MOA: same as cyclosporine but binds to a different immunophilin, FKBP-12 Oral or iv. Absorption < if taken with high fat food.

SE: nephrotoxicity and neurotoxicity(tremor, seizures, hallucination), insulin dependent DM in blacks and Hispanics NO gum hyperplasia, hirsutism

Sirolimus(SRL) Originally called rapamycin Obtained from fermentations of soil mold Equipotent to cyclosporine Prevent renal transplant rejection Given with cyclosporine and glucocorticoid to decrease toxicity of the drugs

MOA; binds to same FK-Binding Protein just like tacrolimus, but instead of binding to calcineurine, it binds to mTOR(Mammalian protein of rapamycin) Thereby blocking the progression of activated T-cells from G1 to S phase of the cell cycle→inhibition of proliferation of T-cells

Pharmacokinetics: oral only SE: HYPERLIPIDEMIA, hypertension, diarrhea Increases nephrotoxicity of cyclosporine when given together

Immunosuppressive antimetabolites Used in combination with glucocorticoids, cyclosporine and tacrolimus --Azathioprine It is a prodrug that is converted first to 6mercaptopurine and then to thionisinic acid→ inhibits purine synthesis required for cell division Lymphocytes are majorly affected SE --Bone marrow suppression, nausea and vomiting NOTE: care should be taken when administered along with allopurinol

others Mycophenolate mofetil: used in heart, kidney and liver transplant because of its ability to prolong graft survival. MOA: hydrolyzed to mycophenolic acid which functions as a reversible uncompetitive inhibitor of IMP dehydrogenase → inhibition of de novo formation of GMP → inhibition of B and T lymphocytes of purines Given orally SE: diarrhea, leukopenia, sepsis, infections & lymphoma

ANTIBODIES Prepared by immunization of rabbits/horses with human lymphoid cells producing a mixture of polyclonal antibiotics directed against a number of lymphocyte antigens Rationale: Prolongs graft survival

Muromonab-CD3 (OKT3) Monoclonal antibody --hybridoma technology Directed against glycoprotein CD3 antigen of human T-cells Used for acute rejection of renal allografts, steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. Binding to the CD3 protein results in disruption of T-lymphocyte function in immune response Circulating T-cells are depleted T-cells usually return to normal within 48 hours of discontinuation of therapy

Antibody administered iv. SE: - cytokine release syndrome following the first dose(mild flu-like illness to life-threatening shock-like reactions), anaphyllactoid reaction, CNS toxicity, ↑CMV infections Premedicate with methyl prednisolone, diphenhydramine & acetaminophen with regards to cytokine release syndrome

adrenocortico steroids- Glucocorticoids first used for immunesuppression both in transplantation and in various autoimmune disorders

Prednisone, methylprednisolone commonly used for transplantation USE; to suppress graft rejection Prednisone or prednisolone used for autoimmune diseases Exact mechanism not known T cells affected the most. Lymphocycte population decreases SE—diabetogenic, osteoporosis, cataracts, Glaucoma. Efforts to reduce/remove steroids are on