1. Zenaida N. Maglaya, MD, FPSECP
ANTI ~ CANCER DRUGS
Zenaida N. Maglaya, MD, FPSECP

2. CANCER
is a disease in which there in uncontrolled multiplication & spread within the body of abnormal forms of the body’s own cells.

3. Special Characteristics of Cancer Cells
Uncontrolled Proliferation
Dedifferentiation and loss of function
Invasiveness
Metastasis

4. Management of Cancer
Surgical
Irradiation
Chemotherapy

5. PHASES OF CELL CYCLE

6. G0 DIFFEREN-TIATION Mitosis M Pre-Synthetic Post –Synthetic G1 G2

7. Cell Cycle Non – Specific (CCNS) Agents
ALKYLATING
AGENTS
Busulfan
Carmustine
Cyclophosphamide
Lomustine
Mechlorethamine
Melphalan
Thiothepa
ANTHRACYCLINES
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
ANTI TUMOR
ANTIBIOTICS
Dactinomycin
Mitomycin
CAMPTOTHECINS
Irinotecan
Topotecan
PLATINUM ANALOGS
Carboplatin
Cisplatin
Oxaliplatin

8. Cell Cycle Specific (CCS) Agents
ANTITUMOR ANTIBIOTIC
Bleomycin
EPIPODOPHYLLO-
TOXINS
Etoposide
Teniposide
TAXANES
Docetaxel
Paclitaxel
ANTIMETABOLITES
Capecitabine
Cladribine
Cytarabine
Fluorouracil
Gemcitabine
Mercaptopurine
Methotrexate
Thioguanine
VINCA ALKALOIDS
Vinblastine
Vincristine
Vinorelbine

9. CANCER CHEMOTHERAPEUTIC AGENTS
I. CYTOTOXIC AGENTS
A. ALKYLATING AGENTS AND RELATED COMPOUNDS
form covalents bonds with DNA
impede DNA replication
B. ANTIMETABOLITES
block or subvert one or more of the metabolic pathways involved in DNA synthesis

10. CANCER CHEMOTHERAPEUTIC AGENTS
C. CYTOTOXIC ANTIBIOTICS
microbial in origin
prevent cell division
D. PLANT DERIVATIVES
affect microtubules and formation of mitotic spindle

12. CANCER CHEMOTHERAPEUTIC AGENTS
II. HORMONES
suppress hormone secretion
antagonize hormone action
III. MISCELLANEOUS AGENTS

13. CLASSIFICATION OF ANTI-CANCER DRUGS

14. POLYFUNCTIONAL ALKYLATING AGENTS
A. NITROGEN MUSTARD
1. CYCLOPHOPHAMIDE
2. CHLORAMBUCIL
3. MECHLORETHAMINE
4. IFOSFAMIDE
5. MELPHALAN
6. ESTRAMUSTINE
B. NITROSOUREA
CARMUSTINE(BNCU)
2. SEMUSTINE (methyl CCNU)
3.LOMUSTINE( CCNU)
4.STREPTOZOCIN

15. POLYFUNCTIONAL ALKYLATING AGENTS
C.ALKYL SULFONATE
1. BUSULFAN
D.AZIRIDINE
1. THIOTEPA
E. TREOSULPHAN

16. RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS
PROCARBAZINE
CISPLATIN
DACARBAZINE
CARBOPLATIN
ALTRETAMINE

17. ANTIMETABOLITES A. FOLATE ANTAGONIST B. PURINE ANTAGONIST
1. METHOTREXATE
B. PURINE ANTAGONIST
1. MERCAPTOPURINE 4. FLUDARABINE
2. THIOGUANINE 5. PENTOSTATIN
3. CLADRIBINE
C. PYRIMIDINE ANTAGONIST
1. FLUOROURACIL 3. CYTARABINE
2. CAPECITABINE 4. GEMCITABINE

18. PLANT ALKALOIDS 1. VINBLASTINE 2. VINCRISITNE 3. VINORELBINE
4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE)
5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN)
6. TAXANES (PACLITAXEL & DOCETAXEL)

19. ANTIBIOTICS 1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN)
2. DACTINOMYCIN(ACTINOMYCIN D)
3. PLICAMYCIN(METHRAMYCIN
4. MITOMYCIN (MITOMYCIN C)
5. BLEOMYCIN
6. EPIRUBICIN
7. MITOZANTRONE

20. HORMONAL AGENTS A. ADRENOCORTICOIDS B. ANDROGENS C. ESTROGENS
1. PREDNISONE
2. HYDROCORTISONE
B. ANDROGENS
1. TESTOSTERONE
2.FLUOXYMESTERONE
C. ESTROGENS
1. DIETHYLSTILBESTROL
2. ETHINYL ESTRADIOL
D. PROGESTINS
1. HYDROXYPROGESTERONE
2.MEDROXYPROGESTERONE

21. HORMONAL AGENTS E. ESTROGEN INHIBITOR : 1. TAMOXIFEN 2. TORIMIFENE
F. ANDROGEN INHIBITOR
1. FLUTAMIDE
2.CYPROTERONE

22. HORMONAL AGENTS G. GONADOTROPIC RELEASING HORMONE AGONIST (GnRH)
1. LEUPROLIDE
2. GOSERELIN
3. NAFERELIN
H. AROMATASE INHIBITORS
1. AMINOGLUTETHIMIDE & TRILOSTANE
2. ANASTROZOLE
3. LETROZOLE
4.EXEMESTANE

23. MISCELLANEOUS ANTI - CANCER DRUGS
ASPARAGINASE (CRISANTASPASE)
2. HYDROXYUREA
3. MITOTANE
4.AMSACRINE
5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN

24. MISCELLANEOUS ANTI - CANCER DRUGS
6. BONE MARROW GROWTH FACTORS
GRANULOCYTE COLONY-STIMULATING FACTOR
(G-CSF, FILGRASTIM)
GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF, SARGAMOSTIM)
AMI FOSTINE (ETHYOL)

25. MISCELLANEOUS ANTI - CANCER DRUGS
MONOCLONAL ANTIBODIES
1. RIFUXIMAB
2. TRASTUZUMAB
RADIOACTIVE ISOTOPES
RADIOACTIVE IODINE-TREATMENT OF THYROID CA
BIOLOGICAL RESPONSE MODIFIER
* INTERFERONS, ALDESLEUKIN, TRETINOIN

26. ALKYLATING AGENTS

27. hepatic microsome P450 mediated cyclophosphamide ACROLEIN…….MESNA
ALKYLATING AGENTS
I. PHARMACOKINETICS
oral or parenteral administration
hepatic microsome P450 mediated cyclophosphamide ACROLEIN…….MESNA
nitrosoureas: highly lipid soluble
unchanged form in urine (cisplatin)
terminated via hepatic metabolism: procarbazine

28. Form reactive molecules…> alkylation (N7 guanine)………>
II. PHARMACODYNAMICS OF ALKYLATING AGENTS
CCNS
Form reactive molecules…> alkylation (N7 guanine)………>
Cross linking of bases, abnormal base pairing & DNA strand breakage
RESISTANCE THRU:
increased DNA repair
decrease drug permeability
production of trapping agents

29. III. CLINICAL INDICATIONS A. CYCLOPHOSPHAMIDE:
ALKYLATING AGENTS
III. CLINICAL INDICATIONS
A. CYCLOPHOSPHAMIDE:
non Hodgskin’s lymphoma, breast & ovarian CA, neuroblastoma
B. MECHLORETHAMINE: Hodgskin ‘s disease (MOPP)
C. CARMUSTINE & LOMUSTINE: brain tumors
D. BUSULFAN: chronic myelogenous leukemia

30. Myelosuppression/ N & V hemorrhagic cystitis (cyclophosphamide)
IV. ADVERSE EFFECTS OF ALKYLATING AGENTS
Myelosuppression/ N & V
hemorrhagic cystitis (cyclophosphamide)
peripheral neuropathy (altretamine))
adrenal insufficiency, pulmonary fibrosis & skin pigmentation (busulfan)

31. RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS
PROCARBAZINE
in Hodgkin’s lymphoma
leukemogenic, teratogenic, mutagenic
N & V, myelosyppression, hemolytic anemia, pulmonary reaction, disulfiram like,skin rashes, CNS depression

32. B.CISPLATIN:
inorganic metal complex
In testicular CA, bladder, lung & ovary CA
Nausea, vomiting, myelosuppression
Nephrotoxicity, neurotoxocity,ototoxicity, anaphylaxis

33. ANTIMETABOLITES

34. .METHOTREXATE PHARMACODYNAMICS
Inhibits dihydrofolate reductase…………..>
INTERFERES w/ thymidylate & purine nucleotide
…> DNA synthesis & cell division block
RESISTANCE:
1. decrease drug accumulation
2.change in drug sensitivity or activity of dihydrofolate reductase
3. decrease formation of polyglutamates

35. METHOTREXATE PHARMACOKINETICS: Oral, IV. IM, intrathecal
CLINICAL USE: choriocarcinoma, acute leukemias, nonHodgskins and cutaneous T cell lymphomas, breast CA; rheumatoid arthritis, psoriasis & abortifacient
ADVERSE EFFECTS; N & V & D, mucositis
bone marrow suppression ; skin effects
reduced by folinic acid (leukoverin rescue)
enhance by salicylates, NSAID, sulfonamides, sulfonylureas

36. MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG)
6 THIOINOSINIC ACID….activated by hypoxanthine - guanine phosphoribosyltransferase (HGPRT)….>
inhibit enzymes involved in purine metabolism
RESISTANCE:
decrease HGPRT activity
increase alkaline phosphatases that inactivate the toxic nucleotides

37. MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG)
PHARMACOKINETCS: oral; urine
6MP metabolism inhibited by allopurinol
CLINICAL INDICATIONS
acute leukemias ; chronic myelocytic leukemias
ADVERSE EFFECTS:
myelosuppression, immunosuppression, hepatotoxicity

38. FLUOROURACIL ( 5FU) Uracil, interferes with DTMP
( 5 FDUMP)………..> thymidylate synthase….> “thymineless death”………..> DNA synthesis inhibition
RESISTANCE:
decreased activation of 5 FU
increased thymidylate synthase activity
reduce drug sensitivity of this enzyme

39. FLUOROURACIL ( 5FU) PHARMACOKINETICS : IV
widely distributed; hepatic metabolism
CLINICAL USES: colorectal, stomach, pancreas, esophagus, liver, bladder, breast, head and neck, liver & ovarian cancers
topical: keratoses & basal cell cancer
ADVERSE EFFECTS: myelosuppression, GIT effects & alopecia, hand & foot syndrome, neurotoxicity

40. CYTARABINE (ARA-C) activated to Ara CTP (inhibitor of DNA polymerase)
most S specific
RESISTANCE
1.decreased uptake
2. decreased conversion to Ara CTP
CLINICAL USE: acute leukemias
ADVERSE EFFECTS: myelosuppression & GIT irritation; neurotoxicity & peripheral neuritis

41. PLANT DERIVATIVES

42. prevent assembly of tubulin dimmers into microtubules
A. VINBLASTINE & VINCRISTINE
* Periwinkle plant
spindle poisons
prevent assembly of tubulin dimmers into microtubules
block formation of mitotic spindle
act on M phase
RESISTANCE: increase efflux of the drug
PHARMACOKINETICS
Parenterally
Hepatic metabolism

43. A. VINBLASTINE & VINCRISTINE
CLINICAL USE
VINCRISTINE: MOPP & COP; acute leukemias, lymphomas, wilm’s tumor, choriocarcinoma
VINBLASTINE: ABVD;, other lymphomas, neuroblastoma, testicular cancer, Kaposi’s sarcoma
VINORELBINE: advance non- small cell cancer
ADVERSE EFFECTS:
VINBLASTINE: GIT distress, alopecia, bone marrow suppression
VINCRISTINE: neurotoxicity, areflexia, peripheral neuritis, paralytic ileus

44. B. ETOPOSIDE & TENIPOSIDE
Podophyllotoxins from May apple root
interacts w/ topoisomerase II….>inhibits mitochondrial electron transport….> increase degradation of DNA
late S and early G2 phase
oral; elimination thru the kidneys
small cell lung CA, prostate & testicular CA
cause bone marrow suppression, GIT effects, alopecia

45. C. TOPOTECAN & IRINOTECAN
from Comptotheca acuminate tree
inhibit topoisomerase I
DNA damage
Topotecan: advanced ovarian cancer, small cell lung cancer
Irinotecan: ,metastatic colorectal CA
Cause: myelosuppression & diarrhea

46. D. PACLITAXEL & DOCETAXEL
Taxanes from Western yew
Prevent microtubule disassembly into tubulin monomers; by IV
Advanced breast and ovarian cancers
Paclitaxel: N & V, myelosuppression, peripheral neuropathy, hypersensitivity rx
Docetaxil: neurotoxicity & bone marrow suppression, fluid retention, rash

47. ANTIBIOTICS

48. A. DOXORUBICIN & DAUNORUBICIN
intercalate between base pairs………> inhibit topoisomerase II….>
generate free radicals …………> block synthesis of RNA & DNA…>
DNA strand scisision
Given IV; excreted in the bile & urine

49. A. DOXORUBICIN & DAUNORUBICIN
DAUNORUBICIN: acute leukemias
DOXORUBICIN: ABVD; myelomas, sarcomas, breast, endometrial, lungs, ovarian & thyroid cancers
CARDIOTOXICITY ( USE DEXRAZOXANE, radical scavenger)
Bone marrow suppression, GIT effects, alopecia

50. B. BLEOMYCIN DNA strand breakage …..……> inhibit DNA synthesis
CCS on G2 phase
USE: testicular cancer & Hodgskin’s lymphoma, lymphomas, squamous cell cancer
Hypersensitivity reaction, pulmonary dysfunction

51. C. DACTINOMYCIN
binds to double-stranded DNA & inhibits DNA dependent RNA synthesis
USE: melanoma & wilm’s tumor
Causes bone marrow suppression, skin & GIT irritation

52. D. MITOMYCIN
Activated to form an alkylating agent…> cross links DNA
IV given; hepatic metabolism
USE: adenocarcinoma of the cervix, stomach, pancreas & lungs
Causes myelosuppression

53. HORMONAL AGENTS

54. HORMONAL ANTICANCER AGENTS
A. GLUCOCORTICOIDS
Prednisone/ Hydrocortisone:
acute & chronic lymphocytic leukemias, hodgskin’s disease, other lymphomas
Fluid retention, hypertension, diabetes, Increase susceptibility to infection

55. HORMONAL ANTICANCER AGENTS
B. SEX HORMONES
estrogen, progestins, androgens: hormone dependent cancers to change the hormone balance
Fluoxymesterone: advanced breast CA
Diethylstilbestrol: prostatic cancer

56. HORMONAL ANTICANCER AGENTS
C. SEX HORMONES ANTAGONISTS
tamoxifen: estrogen receptor oartial agonist
may cause nausea & vomiting, hot flushes, vaginal bleeding, hypercalcemia, ocular, dysfunction& peripheral edema
Flutamide: prostatic cancer
Cause:gynecomastia, hot flushes, hepatic dysfunction

57. HORMONAL ANTICANCER AGENTS
D. GONADOTROPIN-RELEASING HORMONE ANALOGS (GnRh ANALOG)
Leuprolide, Goserelin & nafarellin
inhibit release of pituitary LH & FSH
prostatic cancer
may cause: bone pain, gynecomastia, hematuria, impotence & testicular atrophy

58. HORMONAL ANTICANCER AGENTS
E. AROMATASE INHIBITORS
anastrozole & leterozole
inhibit enzyme that catalyzes the conversion of androstenedione to estrone
advanced breast cancer
diarrhea, nausea, hot flushes, bone & back pain, peripheral edema

59. MISCELLANEOUS ANTICANCER AGENTS

60. MISCELLANEOUS ANTICANCER AGENTS
A. Asparaginase
depletes serum asparagines
used in leukemias & lymphomas
given IV
may cause severe hypersensitivity reactions, acute pancreatitis & bleeding

61. MISCELLANEOUS ANTICANCER AGENTS
B. Mitoxantrone
alkylation of bases
acute leukemias & breast cancer
cause myelosuppression, GIT effects & cardiac arrythmias

62. MISCELLANEOUS ANTICANCER AGENTS
C. Interferons
endogenous glycoproteins with antineoplastic, immunosuppresion & antiviral actions
Use in hairy cell leukemias, chronic myelogenous leukemia, T cell lymphomas
Cause myelosuppression & neurologic dysfunction

63. MISCELLANEOUS ANTICANCER AGENTS
D. Monoclonal Antibodies
RIFUXIMAB
Monoclonal antibody to a surface protein non- Hodgskin’s lymphoma cells
TRASTUZUMAB: monoclonal antibody to a surface protein in breast cancers that over express the HER2 protein
Toxicity: hypersensitivity reactions & myelosuppression
Cardiac dysfunction with trastuzumab

64. STRATEGIES IN CANCER CHEMOTHERAPY
I. Each drug should be active when used alone against the particular cancer
II. The drug should have different mechanism of action
III. Cross resistant between drugs should be minimal.
IV. The drugs should have different toxic effects.

65. SAMPLES OF COMBINATION CHEMOTHERAPY
. HODGKIN’S DISEASE: MOPP / ABVD
2. NON-HODGKIN’S LYMPHOMA: COP
3. TESTICULAR CARCINOMA: PVB
4. BREAST CANCER: CMF/CAF

66. CANCER CHEMOTHERAPY ACRONYMS
ABVD : Doxorubicin (adriamycin),
bleomycin, vinblastine, dacarbazine
CHOP :Cyclophosphamide, doxorubicin
(hydroxydaunorubicin), vincristine
(oncovin), Prednisone
MOPP : Melchlorethamine, vincristine
(oncovin), Procarbazine, Prednisone

67. ACRONYMS COP :Cyclophosphamide, vincristine (oncovin), prednisone
PEB: Platinuml(cisplatin),
etoposide bleomycin
CMF : Cyclophosphamide, methotrexate, Fluouracil
CAF: cyclophosphamide, adriamycin(doxorubicin) , 5 FU

68. THE LEUKEMIAS

69. 1. ACUTE LEUKEMIA CHILDHOOD LEUKEMIA
> ALL: induction: vincristine & prednisone
>remission maintenance: mercaptopurine, methotrexate & cyclophosphamide in various combination
ADULT LEUKEMIA
> AML: cytarabine, mitoxantrone or daunorubicin or idarubicin

70. CML: Imatinib, busulfan, or interferon
2.CHRONIC LEUKEMIA
CML: Imatinib, busulfan, or interferon
in younger patient: bone marrow transplant
CLL: chlorambucil & prednisone
fludarabine

71. THE LYMPHOMAS 1. HODGKIN’S DISEASE MOPP ABVD 2. NON-HODGKIN’S LYMPHOMA
CHOP
> Mitoxantrone & Paclitaxel
MULTIPLE MYELOMA
melphalan & prednisone

72. CARCINOMA OF THE BREAST
Stage I SURGERY
Stage II: positive lymph nodes: SURGERY plus cytotoxic chemo in 8 cycles at one month apart; CMF/CAF; tamoxifen in postmenopausal women
Stage III & IV Palliative
aminoglutethimide, trastuzumab

73. CARCINOMA
WILM’S TUMOR: vincristine lus dactinomycin after surgery
>Methotrexate, cyclophosphamide, doxorubicin
NEUROBLASTOMA: doxorubicin + cyclophosphamide + vincrisitne
CARCINOMA OF THE PANCREAS: gemcitarabine
POLYCYTHEMIA VERA: busulfan, chlorambucil or cyclophosphamide

74. CARCINOMA CHORIOCARCINOMA OF THE UTERUS:
Methotrexate / Etoposide & Cisplatin
CARCINOMA OF THE OVARY: cisplatin & paclitaxel
TESTICULAR NEOPLASMS: PEB
CARCINOMA OF THE PROSTATE
Estrogen, leuprolide & Flutamide
CARCINOMA OF THE THYROID
Radioiodine, doxorubicin & cisplatin

75. CARCINOMA GASTROINTESTINAL CARCINOMAS
Stomach: 5FU plus doxorubicin & mitomycin
Colon: 5 FU plus leucoverin or interferon
MALIGNANT MELANOMA & MISC SARCOMAS:
dacarbazine & cisplain
BRAIN TUMORS
> carmustine, multimodality therapy

76. LUNG CARCINOMA Small cell( SCLC) Non-small cell(NSCLC)
CISPLATIN & TAXANES
Others: methotrexate, vincristine, vinblastine, doxorubicin, mitomycin C

77. THANK YOU VERY MUCH !!! Cast your burden on the Lord.
And He shall sustain you
He shall never permit the
Righteous to be moved.
Psalm 55 : 22