Professional Documents
Culture Documents
Natural Products
In
Cancer Treatments
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
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:
Vinka alkloids
Taxanes
Vinka alkloids
Obtained from periwinkle plant ( Vinca Rosea)
Vincristine, vinblastine, vindesine, vinorelbine
Uses
Structurally # therapeutics indications
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
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
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:
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)
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)
2. Indirect inhibition
adhesion molecules
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)