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Chemotherapeutic

Natural Products
In
Cancer Treatments

Dr. Harshika Patel
Pharmacology and therapeutics II
Date:17/05/2018
Time :2-4 pm
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Antibiotics

 Cellcycle non specific drugs
 Derived from streptomyces species

 MOA:
 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
Actinomycin D/ Dactinomycin:
 First antibiotic for tumor
chemotherapy
Uses:
• in combination with surgery
• soft-tissue sarcomas
• Wilms tumor
• gestational choriocarcinoma

Adverse effects
• bone marrow supression
• Irritant like meclorethamine
• sensitizes to radiation
• inflammation at sites of prior
radiation therapy may occur
• Gastrointestinal adverse effects
Doxorubicin and Daunorubicin
 Doxorubicin
is the hydroxylated analog of
daunorubicin, idarabicin (4-demethoxy analog of
daunorubicin)

Uses :
 Daunorubicin : combination with other agents for
treatment of sarcomas, carcinomas (breast and
lung, ALL, lymphomas
 Daunorubicin and Idarubicin :acute leukemias
MOA
 Have three major actitivies
and affects the S & G2
phase of cell cycle:
1. Intercalation in the DNA
2. Binding to cell membranes
3. Generation of oxygen
radicals
 i.v. infusion only

 Metabolised in liver

 Excreted mainly via hepatic route
(dose modification necessary in
hepatic function failure pt)
 Some of drug eliminated via urine(do
not required dose adjustment in renal
imparement pt*)

AE:
• Irreversible, dose-dependent
cardiotoxicity (liposomal-
encapsulated doxorubicin)
• bone marrow
suppression, stomatitis, and GIt
disturbances
• alopecia
Mitoxantrone
 Analog of doxorubicin
 Lower cardiotoxicity
 Uses: Acute leukemia, CML, Non hodgkins

Mitomycin C
 Highly toxic used only in resistant cancers of
stomach, colon, rectum
 Transformed to form which acts like alkylating agent

Mithramycin
 Reduces blood calcium levels by inhibiting
osteoclasts
 Used in T/t of hypercalcemia with bone metastasis
Bleomycin
 mixture of different
copper-chelating oxidation
glycopeptides
 cell-cycle specific
 causes cells to Liberated
electron form
accumulate in the G2
phase
MOA:

phosphodiester bonds of DNA
1. strand breakage
2. chromosomal abnormalities
Uses :
 Epidermoid cancers of Resistance :
skin,
1. increased levels of
 oral cavity • bleomycin hydrolase/
 genitourinary tract, deamidase
esophagus • glutathione-S-transferase
increased efflux of the drug
 Testicular tumors 2. DNA repair
 Hodgkins lymphoma
PK:
• Administered via various
Adverse effects: route: IV, IM, SC, Intracavitary
 Pneumonitis • Inactivate enz present in liver
& spleen,
 Fatal pulmonary • but low in lung and absent in
fibrosis skin (responsible for toxicities)
 Hyper pigmentation • Excretion thr’ kidney (dose
adjustment necessary in renal
 spares bone marrow impairment pt.)
Microtubule Inhibitors

Vinka alkloids
Taxanes
Vinka alkloids
 Obtained from periwinkle plant ( Vinca Rosea)
 Vincristine, vinblastine, vindesine, vinorelbine
Uses
Structurally # therapeutics indications

VX: acute lymphoblastic leukemia in children, Wilms‘ tumor,
Ewing's soft-tissue sarcoma, Hodgkin's & non-Hodgkin's
lymphomas, rapidly proliferating neoplasms
 Prescribed in several Regimen :
POMP(leukemia), MOPP (Hodgkin's lymphoma)

VBL:
 bleomycin and cisplatin  metastatic testicular carcinoma
 systemic Hodgkin's and non-Hodgkin's lymphomas

VRB:
 advanced non small cell lung cancer (alone/ with cisplatin)
Taxanes
 Paclitaxel & docetaxel
 Plant product obtained from bark of:
Pacific Yew ( Taxus Brevifolia) & European Yew
(Taxus Buccata)
Paclitaxel
 Administered IV PK:
 Use: advanced breast & ovarian • Well distributed
cancer also lungs, esophagus, • Metabolised by
prostrate cancer Liver enz
 Adverse effects: Anaphylactoid CYP450
reaction because of solvent • So biliary excreted
cremaphor
thr feces
 Myalgia, myelosupression,
peripheral neuropathy
• Doses should be
reduced in hepatic
Docetaxel
dysfunction
 I.V.
 Used in refractory breast & ovarian
cancer
 Major toxicity neutropenia may
cause aarrhythmias, hypotension
Enzyme (L- Asparginas )
 Isolated from E.coli A/E:
 Use: childhood ALL • Hepatic damage
(combine with VX / • Hypersensitivity (bcz it is
prednisone), high foreign protein),
grade lymphomas hemorrhage
• Hyperglycemia,
 Dose : 6000 to headache,
10000U/kg IV daily hallucinations, confusion,
for 3-4 weeks coma

 PK:
• IM/IV
• Destroyed by gastric
enzymes
MOA
Epipodophyllotoxins
 Etoposide& tenoposide
 Semisynthetic derivatives of podophyllotoxins
podophyllum peltatum (plant glycoside)
Etoposide:
 Act in late S & G2 phase
 Inhibit topoisomerase II which
results in breakage of DNA
strands & cell death

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
 second-line drug in ALL
(teniposide)
PK:
 IV/ orally, teniposide only IV
 highly bound to plasma proteins
 distribute thr’ the body
 Poorly penetrate CSF (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
Camptothecin analogs
 Derived from camptotheca accuminata
 Inhibit Topoisomerase I: No resealing of DNA after
strand has untwisted
Topotecan: –
 Used in metastatic ovarian cancer
 Major toxicity is bone marrow depression

Irinotecan: (more potent)
 SN38 Metabolites-- > have more potency then
irinotecan
 Used in metastatic cancer of colon/rectum
 Toxicity: diarrhoea, neutropenia,
thrombocytopenia, cholinergic side effects
Targeted Therapy
1. Protein kinase inhibitors
2. Epidermal growth factor receptor inhibitors
3. HER 2 / neu inhibitors
4. Inhibitors of angiogenesis
5. Proteasome inhibitors
6. MTOR inhibitors
7. Biological response modifiers:
8. Colony stimulating factors
 To block the fundamental mutations that cause
specific cancers:
1. aberrant growth factor receptors
2. dysregulated intracellular signaling pathways
3. defective DNA repair and apoptosis
4. tumor angiogenesis

 mainly treated by
1. monoclonal antibodies that attack cell surface
receptors and antigens
2. synthetic small molecules that enter cells and
engage critical enzymes
Protein kinase inhibitors
 Inhibitor of BCR-ABL kinase:
Imatinib, Dasatinib & Nilotinib
 treatment of chronic myelogenous leukemia
(CML), a pluripotent hematopoietic stem
cell disorder characterized by the t(9:22)
Philadelphia chromosomal translocation
 Translocation results in the Bcr-Abl fusion
protein, the causative agent in CML
 inhibitor of the tyrosine kinase domain of the
Bcr-Abl oncoprotein and prevents the
phosphorylation of the kinase substrate by
ATP
 administered orally and is well absorbed
 highly protein-bound in plasma
 metabolized in the liver
 elimination of metabolites occurs mainly in feces via
biliary excretion

Uses : first-line therapy in chronic phase CML, in blast crisis,
 second-line therapy for chronic phase CML that has
progressed on prior interferon therapy.
 Also gastrointestinal stromal tumors expressing the ckit
tyrosine kinase

AE: GI problems, fluid retention,
Nilotinib: cardiotoxicity (causation with cardiac ill pt)
Myelosuppression , heptotoxicity
Epidermal growth factor
receptor inhibitors
 Also known as ErbB1 or HER1

Gefitinib (single drug rx)
 Non small cell lung cancer that has failed to respond to other
therapy

 Orally absorbed
 Metabolised by liver enz (CYP 450)and co enz (CYP 3A4)
 Metabolites have some anti tumor activity
 Elimination of drug and its metabolites in feces

 AE: diarrhea, nausea, and acne-like skin rashes
 A interstitial lung disease acute dyspnea with cough (rare
but fatal AD)
Erlotinib:
 Inhibits EGFR tyrosine kinase

 second-line treatment of patients with locally
advanced or metastatic non–small cell lung cancer
 Used as a Single agent
 first-line rx : locally advanced / metastatic pancreatic
cancer in combination with gemcitabine

 AE: diarrhea, acne form rash, anorexia, fatigue
 Closely monitored pt with hepatic dysfunction
 GI perforation, renal failure, arterial thrombosis,
microangiopathic hemolytic anemia(rare but fatal)
HER2/neu Inhibitors

 Both antibodies (trastuzumab)

 small molecules (lapatinib)

have antitumor effects in patients with HER2-positive
breast cancer
Trastuzumab (Herceptin)

 recombinant DNA, Combination with paclitaxel, MB
cancer

 Precise MOA is unclear, however, work by Targets
the extracellular domain of the HER2 growth
receptor that has intrinsic tyrosine kinase activity
 Herceptin is an anti-cancer antibody that acts on
HER2 receptor, which is overexpressed in breast
cancer  Inhibits the proliferation of cells that
overexpress the HER2 protein  decreasing the
number of cells in the S phase.
 An induction of antibody-dependent cytotoxicity
 a decrease in angiogenesis due to an effect on
vascular endothelial growth factor

 This can reduce the rate of relapse of breast
cancer by 50% during the first year.

AE:
 congestive heart failure (worsen with
anthracyclin),caution with cardiac dysfunction pt
 fever and chills, headache, dizziness, nausea,
vomiting, abdominal pain, and back pain
(tolerated)
lapatinib
 Small molecules
 inhibit receptor tyrosine kinase activity of ErbB2
(HER2/neu)  antitumor activity in pt  who
developed progressive disease on trastuzumab
(synergism)

 Uses : HER2-amplified, trastuzumab-refractory breast
cancer

 PK: Orally active, hepatic metabolism thr’ CYP 3A4 ,
metabolites have inhibitory activity towards both ErbR
1/ 2 , excreted via biliary route in feces

 AE: mild diarrhea, cramping, and exacerbation of
gastro-esophageal reflux, acne form rash*
 Non cardiotoxic
Inhibitors of angiogenesis
 induction of new blood vessel formation 
angiogenesis  essential property of cancers
 Cancer cells secret
 angiogenic factors
 induce the formation of new blood vessels
 Ensure the flow of nutrients to the tumor cells

 secreted Angiogenic factors by tumors:
1. VEGF (vascular endothelial growth factor),
2. FGF (fibroblast growth factor),
3. TGF- (transforming growth factor ) and
4. PDGF (platelet-derived growth factor).
Bevacizumab
a new class of mAB anticancer drugs called
antiangiogenesis agents.
 First-line drug against metastatic colorectal cancer
 with carboplatin + paclitaxel = non–small lung
cancer by 2 months. Likewise,
 with FOLFOX (5-FU, leucovorin, and oxaliplatin) or
FOLFIRI (5-FU, leucovorin, and irinotecan) improves
survival by 5 months in metastatic colon cancer
 infused IV
MOA:
It attaches to vascular endothelial growth factor in tumor cells
 stops  the formation of new blood vessels  Without new
blood vessels, tumors do not receive oxygen and essential
nutrients for growth 

ADVERSE EFFECTS:
 hypertension, stomatitis, and diarrhea
 Less common:
 bleeding in the intestines,
 protein in the urine, and
 heart failure
 Rare serious side effects : bowel perforation, opening of
healed wounds, stroke
Sunitinib /Sorafenib
 competitively inhibits  the binding of ATP  to the
tyrosine kinase domain on the VEGF receptor-2 (VEGFR
1,3, PDGFR-B, C-KIT)

 Advanced & metastatic renal-cell cancer
 50mg/kg, daily orally
 Metabolised by liver enz3A4
 Biliary excretion

AE: bleeding, hypertension, proteinuria
 arterial thromboembolic
 intestinal perforation
 Hypothyroidism
 Bone marrow suppression and diarrhea,
 Neutropenia, congestive heart failure (RARE)
Thalidomide / lenalidomide
 Immunomodulators have antitumor effects
 MOA unclear
 However ,preclinical in vitro and in vivo studies
give some ideas about mechanism of action,
such as:
1. anti-proliferative/pro-
apoptotic antitumor
effects inhibit the anti-
apoptotic effects of NF-B
and the anti-apoptotic
Bcl-2 family member
A1/Bfl-1

2. Indirect inhibition
adhesion molecules

3. Inhibition of IL-6, TNF
production, release, and
signaling, leading to anti-
angiogenic effects

4. Immunomodulation
through enhancement
(NK) and T cell–mediated
cytotoxicity
S & R enantiomers are available
 R isomer: biological active and teratogenicity
 S isomer : sedative effect
 Orally active, 200-1200 mg/day rx of MM, escalated
by 200 mg/day every 2 weeks (dose limiting
toxicity)
 distributed well in most of the organs and tissues
(without plasma pro bound)
 Peak level reached at 3-4 hours, t1/2 : approx 6
hours
 Elimination via kidney
AE: CNS depression (sedative property), nephropathy
Dose limiting side effects: sedation, fatigue,
constipation, sensory neuropathies
lenalidomide
 Oral: <200 mg daily
 little sedation, constipation, or neuropathy
 hepatotoxicity and renal dysfunction
(rare)
Proteasome Inhibition: Bortezomib
 IV bolus
 Plasma t1/2: 5hours
 Metabolised by CYP3A4
hydroxylation
 Eliminate in the urine
(dose adjustment not required in
renal impairement pt)

USES: MM and replapsed MM

AE: thrombocytopenia, fatigue,
peripheral neuropathy, neutropenia,
anemia, vomiting, diarrhea, limb
pain, dehydration, nausea, or
weakness, diabetes (rare)