1. ANTICANCER DRUGS & IMMUNOMODULATORS

2. “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.

3. 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.

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

5. 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.

6. 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

7. 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

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

9. 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 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.

10. Benefits of chemotherapy
CURE
PALLIATION
PROLONGATION OF USEFUL LIFE

11. 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

12. 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

13. 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

14. 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

15. 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

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

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

18. 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

19. 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

20. Alkylating Agents Carmustine Lomustine Cyclophosphamide Ifosfamide
Mechlorethamine
Streptozotocin
Mitomycetin
Dacarbazine
Chlorambucil

21. 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

22. 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,

23. 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

24. 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

25. 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

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

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

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

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

30. 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

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

32. 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

33. 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

34. Mitotic Inhibitors Also called Microtubule inhibitors Vincristine
Vinblastine
Paclitaxel
Navelbine

35. 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.)

36. 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

37. 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

38. 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

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

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

41. Antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Idarubicin
Plicamycin
Mitoxantrone

42. 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

43. 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.

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

45. 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

46. 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

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

48. 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

49. 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

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

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

52. 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

53. 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,

54. 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.

55. 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

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

57. 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.

58. Trastuzumab
Rituximab
Bevacizumab
cetuximab

59. 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

60. 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.

61. 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

62. IMMUNOSUPPRESSIVE DRUGS

63. 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.

64. 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).

65. 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)

66. 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.

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

68. 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.

69. 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

70. 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.

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

72. 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

73. 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

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

75. 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

76. 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

77. 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

78. 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

79. 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

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

81. 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