anthracyclines, vinca alkloids, taxes, podophylotoxines, enzymes in cancer treatment

1. Natural
Chemotherapeutic
Agents
Dr. Harshika Patel
KeMU
MEDB 336 Basic pharmacology and toxicology

3. Antibiotics
• Cell cycle non specific drugs
• Derived from streptomyces species
• Used in practice : anthracyclines, dactinomycin, bleomycin, and
mitomycin
• General MOAs:
Intercalation in the DNA between adjoining nucleotide pairs 
blocks DNA & RNA synthesis
Generation of oxygen radicals which mediate single strand
scission of DNA
Action on Topoisomerase II

4. Anthracyclines antibiotics:
Doxorubicin and Daunorubicin
• Doxorubicin is the hydroxylated analog
of daunorubicin  both drugs are US-
FDA approved
• A 4-demethoxy analog of
daunorubicin idarubicin, and
Epirubicin, Mitoxantrone are in clinical
practice

5. MOA
• Have four major activities and affects
the S & G2 phase of cell cycle:
1. Intercalation in the DNA 
consequent block DNA, RNA
synthesis  DNA strand break
2. inhibition of topoisomerase II
3. Binding to cell membranes  and to
alter fluidity and ion transport
4. Generation of oxygen radicals
Causes of
cardiotoxicity

6. • IV infusion only
• Metabolised in liver:
• The hydroxylated metabolite  is in active
form, while…
• The aglycone molecules  inactive
• 50% of drug excreted mainly via hepatic route
(dose modification required in ____________?)
• Some of drug eliminated via urine(do not
required dose adjustment in renal impairment pt)
• Usually administered on an
• every-3-week schedule
• Alternative schedules of administration such as low-
dose weekly or 72–96 hour continuous infusions 
leads equivalent clinical efficacy with low overall
toxicity.

7. Clinical uses
• Doxorubicin – broad spectrum
anticancer
• Breast, endometrium, ovary
• Testicle
• Thyroid
• Stomach, bladder,
• liver, and lung
• In soft tissue sarcomas
• several childhood cancers:
• Neuroblastoma
• Ewing's sarcoma
• Osteosarcoma
• Rhabdomyosarcoma
• Hematologic malignancies:
• Acute lymphoblastic leukemia
• Multiple myeloma
• Hodgkin's and non-Hodgkin’s
lymphomas
• Responses and remission duration
tend to be improved with
combination regimens

8. •Daunorubicin – narrow spectrum
• acute myeloid leukemia
•Idarubicin: semisynthetic anthracycline glycoside analog
of daunorubicin
• combination with cytarabine* AML
•Epirubicin: doxorubicin analog
• Uses: component of adjuvant therapy of early-stage, node-
positive breast cancer
• Currently  Metastatic breast cancer

9. Overall Adverse effects
• Cardiotoxicity  occur in two forms
• Acute cardiotoxicity:
• Within the first 2–3 days
• Arrhythmias or conduction abnormalities, other ECG changes, pericarditis, and
myocarditis
• Transient and asymptomatic in most cases
• Chronic cardiotoxicity:
• Dose-dependent, dilated cardiomyopathy associated with heart failure.
• Toxicity increased with production of free radicals within the myocardium
• Bone marrow suppression: neutropenia(more observed),
thrombocytopenia(rarely)
• Stomatitis, and GIT –disturbances
• Alopecia

10. Actinomycin D/ Dactinomycin:
•First antibiotic for tumor chemotherapy
Uses: in combination with surgery used to treat
• Soft-tissue sarcomas
• Wilms tumor (child)
• Gestational choriocarcinoma
Mode of action:
•It binds tightly to double-stranded DNA through
intercalation between adjacent guanine-cytosine base
pairs and inhibits all forms of DNA-dependent RNA
synthesis.

11. Adverse effects
•Bone marrow supression
•Irritant like meclorethamine
•Sensitizes to radiation
•Inflammation at sites of
prior radiation therapy may
occur
•Gastrointestinal adverse
effects

12. Mitomycin C
• Isolated from Streptomyces Caespitosus
• Biotransformed intermediate acts like alkylating agent  cross-links
DNA
• On conducive environment convert into reduce form and become
radiosensitive
• Use in combination with radiation therapy to attack hypoxic tumor
cells
USES:
• DOC for squamous cell cancer of the anus (fluorouracil and
radiation therapy)
• Squamous cell carcinoma of the cervix
• Adenocarcinomas of the stomach, pancreas, and lung

13. Adverse effects
•Hemolytic-uremic syndrome: microangiopathic
hemolytic anemia, thrombocytopenia  renal failure
•Interstitial pneumonitis
Mithramycin: RNA synthesis inhibitor
•Reduces blood calcium levels by inhibiting osteoclasts
•Used in T/t of hypercalcemia with bone metastasis

14. Mitoxantrone
• It is di-hydroxy-anthracenedione, an anthracene compound 
resembles the anthracycline ring.
• It binds to DNA to produce strand breakage and inhibits both DNA
and RNA synthesis.
• Currently used for tx of
• Advanced, hormone-refractory prostate cancer and
• Low-grade non-Hodgkin's lymphoma
• Breast cancer,
• In pediatric and adult acute myeloid leukemias.
• The plasma half-life: ~75 hours  predominantly excreted via the
hepatobiliary route  in feces

15. Adverse effects:
•Myelosuppression with leukopenia: dose-limiting
toxicity
•Mild nausea and vomiting,
•Mucositis
•Alopecia
•Both acute and chronic cardiac toxicity (rare)
•A blue discoloration of the fingernails, sclera, and
urine can be observed up to 1–2 days after drug
therapy.

16. Bleomycin
• Mixture of different copper-
chelating glycopeptide
• Cell-cycle specific
• Causes cells to accumulate
in the G2 phase
MOA:
oxidation
Liberated
electron form
phosphodiester bonds of DNA
1. strand breakage
2. chromosomal abnormalities

17. Mechanism and Resistance
• Bleomycin is a small peptide contains
• a DNA-binding region
• an iron-binding domain at opposite ends of the molecule
• It acts by binding to DNA  results
• In single-strand and double strand breaks  free radical formation 
inhibition of DNA biosynthesis
• Resistance :
1. increased levels of
• bleomycin hydrolase/ deamidase
• glutathione-S-transferase
2. increased efflux of the drug
3. DNA repair

18. Uses :
• Hodgkins, non-hodgkins lymphoma, germ
cell tumor
• Head, neck cancer
• Epidermoid cancers of skin, cervix, vulva
• Sclerosing agent for malignant pleural
effusions and ascites
• Oral cavity, esophagus cancer
• Testicular tumors
Adverse effects:
• Pneumonitis
• Fatal pulmonary fibrosis
• Hyper pigmentation
• spares bone marrow
PK:
• Administered via various route:
IV, IM, SC, Intracavitary
• Bleomycin -inactivate enz
present in liver & spleen,
• but low in lung and absent in
skin (responsible for toxicities)
• Excretion thr’ kidney (dose
adjustment necessary in renal
impairment pt.)

19. EXTRA
• FIDAXOMICIN - find out the activity as anticancer drug?
• Plicamycin: also known as brilliant-mycin.
• Bind to DNA, inhibit the synthesis of RNA, and act on cell proliferation at each
stage
• clinical treatment of testicular embryonal cancer, various malignant cancers
caused by hypercalcemia, also in glioma and lymphoma
• gastrointestinal reactions, bleeding, liver, kidney damage
• Salinomycin:
• It interferes with transmembrane potassium potential
• Shown activity against many types of cancer stem cells (CSCs), and sensitizes
multidrug-resistant human cancer cells

20. Microtubule Inhibitors
Vinka Alkaloids
&
Taxanes

21. Vinka alkloids
•Obtained from periwinkle plant ( Vinca Rosea)
•Asymmetrical dimeric compounds formed by condensation
of the vindoline and catharanthine subunits
•Vincristine, vinblastine, vindesine, vinorelbine

23. Pharmacokinetics
• The liver cytochromes extensively metabolize all three agents
• The metabolites are excreted in the bile (small fraction of a dose
(<15%) found in urine unchanged)
• With hepatic dysfunction (bilirubin >3 mg/dL)  reduced the dose
(50 -75%)
• The pharmacokinetics of each of the three drugs are similar, except
an elimination t1/2 of
• 20 hours for vincristine,
• 23 hours for vinblastine
• 24 hours for vinorelbine

24. Uses: Structurally # therapeutics indications
Vx:
• With prednisone for remission in all childhood cancers
• Wilms‘ tumor, Ewing’s tumor,
• Soft-tissue sarcoma, Hodgkin's & non-Hodgkin's lymphomas, multiple
myeloma and rapidly proliferating neoplasms rhabdomyosarcoma,
neuroblastoma
Prescribed in several regimen :
POMP(leukemia), MOPP (hodgkin's lymphoma)
Vbl:
• With bleomycin and cisplatin  metastatic testicular carcinoma
• Systemic Hodgkin's and non-Hodgkin's lymphomas
Vrb:
• Advanced non small cell lung cancer (alone/ with cisplatin) and breast cancer

25. IMPORTANT NOTES ON VX *(PROTOTYPE AGENT)
• Formation of mitotic spindles, microtubules are found in high concentration
in the brain  contribute to other cellular functions such as
• Movement
• Phagocytosis
• Axonal transport
• These feature of alkaloids cause neurotoxicity
Specially with VX: dose –limiting toxicity neurotoxicity, peripheral
sensory neuropathy
• Autonomic nervous system dysfunction  orthostatic hypotension, sphincter
problems, and paralytic ileus—cranial nerve palsies, ataxia, seizures, and coma
(observed)
• BM suppression is milder than vinblastine
• Develop SIADH

26. Adverse effects:
• (++)myelosuppressive effects of vincristine  valuable
component of several combination therapy regimens for
leukemia and lymphoma,
• Less severe neurotoxicity by vinblastine reveal good
effect in lymphomas and with cisplatin in  testicular
cancer.
• Vinorelbine with (+)neurotoxicity and also
(+)myelosuppression  intermediate toxicity profile
Extravasation is still there  IV infusion related

28. Taxanes
• Paclitaxel & docetaxel
• Plant product obtained from bark of:
Pacific Yew ( Taxus Brevifolia) & European Yew
(Taxus Baccata)

29. Microtubule assembly disturb by paclitaxel without any
help of microtubule-associated proteins and guanosine
triphosphate  which is essential for normal function of
microtubules formation

30. Pharmacokinetics : taxanes
• Bcz of poor aqueous solubility  It was reformulated and approved by
the U.S.FDA in 2005 as an albumin-bound nanoparticle solution for
infusion nab-paclitaxel
• Inhibition of mitosis differing from the vinca alkaloids and colchicine
derivatives in that they bind to a different -tubulin site  and inhibit
microtubule formation
• Well distributed
• Metabolised by Liver enz CYP2C8 and CYP3A4
• So biliary excreted thr feces (90%)
• Doses should be reduced in hepatic dysfunction

31. Formulations

32. Paclitaxel
• Administered IV  over 30 minutes at 260 mg/m2 every 3 weeks
• Use: solid tumors cancer: advanced breast & ovarian, non small cell
lungs, esophagus, prostrate -bladder, head and neck, and AIDS-
related Kaposi's sarcoma
• Adverse effects: Anaphylactoid reaction because of solvent
cremaphor
• Hypersensitivity: red’ by premedication with dexamethasone,
diphenhydramine, and an H2 blocker
• Nab-paclitaxel  doesn’t need pretreatment but high rate of peripheral
neuropathies
• Myalgia, myelosupression (neutropenia*), peripheral neuropathy

33. Docetaxel
• I.V.
• Used in refractory breast & ovarian and non-small cell
lung cancer (second-line therapy)
• Also in head, neck and Gastric cancer
• Major toxicity neutropenia and lesser extent to cause
peripheral neuropathies
• May cause arrhythmias, hypotension

34. Epothilones
• Resembles the taxanes in their action but has limited cross-resistance
with taxanes
• Ixabepilone  only approved epothilones in the U.S.
• USES: Ixabepilone plus capecitabine compared to capecitabine alone in
• Metastatic breast cancer resistant
• Pretreated with anthracyclines and resistant to taxanes
• Monotherapy in metastatic breast cancer  with same above drugs
• ADR: Neutropenia, peripheral sensory neuropathy, fatigue, diarrhea,
and asthenia
• Contraindicate in BMS pt.  has very potent property to cause BM
suppression and hepatic dysfunction pt.

35. Enzyme (L- Asparaginase )
• Isolated from E.coli
• Use: childhood ALL (combine
with VX / prednisone), high
grade lymphomas
• Dose : 6000 to 10000U/kg IV
daily for 3-4 weeks
• PK:
• IM/IV
• Destroyed by gastric
enzymes
A/E:
• Hepatic damage
• Hypersensitivity (bcz it is
foreign protein),
hemorrhage
• Hyperglycemia,
headache, hallucinations,
confusion, coma
Crisantapase….?

36. Mechanism of Action
• In untreated patients L- asparagine is used by
cancer cell for protein synthesis from blood.
• In the presence of L- Asparaginase its get converted
into L- Aspartic acid and ammonia and block the
protein synthesis pathways in some cancer cells.

37. Topoisomerase I & II
inhibitors
Epipodophyllotoxins
Camptothecin analogs

38. Epipodophyllotoxins
• Etoposide & tenoposide approved clinically in the USA
only
• Semisynthetic derivatives of podophyllotoxins
podophyllum peltatum mayapple root(plant glycoside)

39. Etoposide:
• Act in late S & G2 phase
• Causes DNA breaks by affecting DNA
topoisomerase-2 function
• While the cleaving of double stranded
DNA is not interfered but the
consequent resealing of the strand is
prevented
Resistance :
• By presence of the multidrug-resistant P-
glycoprotein or by mutation of the enzyme
• Uses: – Testicular tumors (with bleomycin
and cisplatin) , squamous cell cancer of
lungs, Hodgkin’s, non-Hodgkin's
lymphomas, and gastric cancer
• Second-line drug in ALL (teniposide)

40. PK:
• IV/ orally, teniposide only IV
• Drug is water insoluble and formulated in a Cremophor vehicle for clinical
use
• Highly bound to plasma proteins
• Distribute thr’ the body
• Poorly penetrate CSF (but teniposide has some activity against gliomas
and neuroblastomas)
• Metabolised by liver enzyme  then converted to glucuronide and
sulfate conjugates excreted in urine
AE: Dose limiting Myelosupression (may cause leukemias)
• Alopecia, anaphylactic reactions, nausea, and vomiting

41. Camptothecin analogs
•Derived from Camptotheca accuminata
•Inhibit Topoisomerase I enz  resulting No resealing
of DNA after strand has untwisted
Topotecan: –
•Used in metastatic ovarian cancer(who have failed
platinum-based)
•second-line therapy of small cell lung cancer
•Major toxicity is bone marrow depression

43. Irinotecan:
•More potent and a prodrug covert into liver by the
carboxylesterase enzyme to  SN38 Metabolites 
have more potency than irinotecan
•Uridine diphosphate-glucuronosyltransferase-1A1
(UGT1A1), converts SN-38 to its inactive derivative
•Polymorphisms of this enzyme are associated with
familial hyperbilirubinemia syndromes  Crigler-Najjar
syndrome and Gilbert syndrome*

44. Contd’…
•Excreted thr’ bile and feces while topotecan is
eliminate thr’ kidney (dose reduction is required
____?)
•Used in metastatic cancer of colon/rectum as second-
line monotherapy who have failed fluorouracil-based
therapy
• And first choice when combine with fluorouracil and
leucovorin
•Toxicity: diarrhoea* (early and late phase),
neutropenia, thrombocytopenia, cholinergic side
effects

45. RAPID QUIZ
RESISTANCE
DEFINITION
PATHOLOGY
COMMON
TOXICITY
PLATINIUM
COORDINATING
AGENTS?
ANTI-
METABOLITING
AGENTS?
WHAT’S
ALKALYTING
AGENTS?
CLASSIFICATION
• METHOTREXATE
• 6-THIOGUANINE
MOLECULES
• 5-FC