anti cancer plant alkaloid Flashcards
Vinblastine
MECHANISM OF ACTION
HOW IT IS EXCRETED
DOSE ADJUSTMENT IN LIVER TOXICITY
CLINICAL USE
SIDE EFFECTS
Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea .
Its mechanism of action involves inhibition of tubulin polym-
erization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death.
Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the hepatobiliary system. As such, dose modification is required in the setting of liver dysfunction.
The main adverse effect include
nausea and vomiting, bone marrow suppression, and alopecia.
This agent is also a potent vesicant, and care must be taken in its admin-istration
It has clinical activity in the treatment of Hodgkin’s and
non-Hodgkin’s lymphomas, breast cancer, and germ cell cancer, kaposi sarcoma
VINCRISTINE
CLINICAL SPECTRUM IS DIFFERENT THATN BLASTINE
EFFECTIVE IN HEMATOLOGICAL SUPRESSIONS
Vincristine+ prednisone f
remission induction in acute lymphoblastic leukemia in children.
It is also active in various hematologic malignancies such as
Hodgkin’s and non-Hodgkin’s lymphomas, and multiple myeloma,
and in several pediatric tumors including rhabdomyosarcoma,
neuroblastoma, Ewing’s sarcoma, and Wilms’ tumor.
VINCRISTINE
SIDE EFFECTS
ANS DYSFUNCTION
NEUROTOXICITY IS LESSER
The main dose-limiting toxicity is neurotoxicity, usually expressed
as peripheral sensory neuropathy, although autonomic nervous
system dysfunction with orthostatic hypotension, urinary retention,
and paralytic ileus or constipation, cranial nerve palsies, ataxia, seizures, and coma has been observed. While myelosuppression occurs, it is generally milder and much less significant than with vinblastine
.OTHER ADR that develop is the syndrome of inap-
propriate secretion of antidiuretic hormone (SIADH).
ALOPECIA
Leukopenia, GI disturbances, anorexia,dermatitis, myelotoxicity
and neurotoxicity.
ETOPOSDIE
DERIVATIVE OF
FORMULATIONS AND DOSAGE FORM
SITE OF ACTION
SIDE EFFECTS
Etoposide is a semisynthetic derivative of podophyllotoxin, which
is extracted from the mayapple root ( Podophyllum peltatum ).
Intravenous and oral formulations of etoposide are approved for
clinical use in the USA. The oral bioavailability is about 50%,
requiring the oral dose to be twice that of an intravenous dose. Up
to 30–50% of drug is excreted in the urine, and dose reduction is
required in the setting of renal dysfunction. The main site of
action is inhibition of the DNA enzyme topoisomerase II.
Etoposide has clinical activity in germ cell cancer, small cell and non-small cell lung cancer, Hodgkin’s and non-Hodgkin’s lymphomas, and gastric cancer.
In addition, it is effective in high-doseregimens in the transplant setting for breast cancer and lymphoma
PACLITAXEL
WEIRD MECHANISM OF ACTION
Paclitaxel is an alkaloid ester derived from the Pacific yew ( Taxusbrevifolia ) and the European yew ( Taxus baccata ). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This
promotion of microtubule assembly by paclitaxel occurs in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division.
CLINICAL ACTIVITY
Paclitaxel
Paclitaxel has significant activity in a broad range of solid tumors, including ovarian, advanced breast, non-small cell and
small cell lung, head and neck, esophageal, prostate, and bladder
cancers and AIDS-related Kaposi’s sarcoma.
It is metabolized
extensively by the liver P450 system, and nearly 80% of the drug
is excreted in feces via the hepatobiliary route. Dose reduction is required in patients with liver dysfunction.
effectiveness of vincristine along with other agents
The most important clinical use of vinblastine/vincristine is with
Bleomycin and Cisplatin in the curative therapy of metastatic testicular
tumors.
It is also active in Kaposi’s sarcoma, neuroblastoma and Hodgkins’ disease
as well as carcinoma of breast and choriocarcinoma.
mechanism of resistance of alkaloids
The antitumor effects are blocked by multidrug resistance mediated
by mdr gene and its glycoprotein, a membrane efflux transporter.
Tumors cells become cross resistant to a wide range of similar agents
like epipodophyllotoxins, anthracyclines.
Resistance result in chromosomal abnormalities.
paclitaxel uses and toxicity
Therapeutic uses
Effective in metastatic ovarian and breast cancer.
Toxicities
Bonemarrow suppression, neutropenia, peripheral neuropathy
ETOPOCSIDE SLIDES
Etoposide
Drug form ternary complex with topoisomerase-II and DNA. This result in
double strand DNA break. The drug-enzyme complex remained bound with to
free end of the broken DNA strand, leading to its accumulation. Cell division
blocks in the S and G2 phase of cell cycle.
Etoposide is clinically effective in testicular cancer, non-Hodgkin’s lymphoma
and in small cell lung cancer in combination therapy(bleomycin and cisplatin).
Toxicities
Hypotension and bronchospasm if administered fastly, myelosuppression,
stomatitis, diarrhea, alopecia, Hepatic toxicity
Dactinomycin
Uses
Toxicities
First crystalline antibiotic isolated from species of Streptomyces.
Drug binds to DNA, dactinomycin-DNA complex inhibit transcription of DNA
by blocking DNA-dependent RNA polymerases. Additionally this drug causes
single strand break.
: treatment of rhabdomyosarcoma and Wilm’s tumors in children
incombination with vincristine and cyclophosphamide.
: Hematopoitic suppression, pancytopenia, ulceration.
bleomycin
Well known as DNA cleaving group.
It is a mixture of two copper chelating peptides like bleomycin A2 and B2.
Bleomycin binds to DNA through its amino terminal peptide and the
activated complex generates free radicals that are responsible for DNA
strand breakage.
The fragmentation of DNA seems to be due to oxidation of a
DNA-bleomycin Fe (II) complex that act as a ferrous oxidase. This transfer
electrons from Fe+2 to molecular oxygen that leads to chromosomal
abberations (chromatid break, gaps /fragments).
Bleomycin causes accumulation of cells in the G2 phase of cell cycle.
Distribution and resistance of bleomycin
Bleomycin is degraded by a specific hydrolase found in liver. This
activity is low in skin and lung contributing toxicity.
Resistance occur due topresence of high level of hydrolase activity
Decreased uptake
Repair of strand break
Drug inactivation by thiols or thiol-rich proteins
Clinical uses
Side effects
Bleomycin is effective in germ cell tumors of testis and ovary in combination with cisplatin and vinblastine.
In combination (ABVD- Adriamycin, bleomycin, vinblastine, dacarbazine)
also effective in squamous carcinoma of head, neck, esophagus, Hodgkins
and non-Hodgkins lymphoma.
Toxicities:
Hyperpigmentation, hyperkeratosis, pulmonary toxicity, anorexia.
