nitrosurea Flashcards
oral administration of lomustine
After oral administration of lomustine, peak plasma levels
of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma.
MAO OF NITROUREAS
Although the majority
of alkylations by the nitrosoureas are on the N7 position of guanine in DNA, the critical alkylation responsible for cytotoxicity
appears to be on the O6 position of guanine, which leads to G-C
crosslinks in DNA
drug having importance in pancreas cancer
naturally occuring sugar containing streptozocin, is interesting because it has minimal bone mar-
row toxicity. This agent has activity in the treatment of
insulin-secreting islet cell carcinoma of the pancreas.
why nitrosureas arae effective against brain tumour
The nitrosoureas are highly lipid-soluble
and are able to cross the blood-brain barrier, making them effective in the treatment of brain tumors.
Procarbazine administration and therapeutics
an orally active methylhydrazine derivative, and in
used in combination regimens for
Hodgkin’s and non-Hodgkin’s lymphoma as well as brain tumors.
The precise mechanism of action of procarbazine is uncertain;
however, it inhibits DNA, RNA, and protein biosynthesis; pro-longs interphase; and produces chromosome breaks.
metabolites of procarbazine
Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H 2O 2
, which may be responsible for DNA strand scission. A variety of other drug metabolites are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO)
inhibitor, and adverse events can occur when procarbazine is given
contraindication of procarbazine
Toxicity of procarbazine
sympathomimetic
agents, tricyclic antidepressants, antihistamines, central nervous system depressants, antidiabetic agents, alcohol, and tyramine-
containing foods.
There is an increased risk of secondary cancers in the form of
acute leukemia, and its carcinogenic potential is thought to be higher than that of most other alkylating agents.
primary binding site of platinum analogs
As such, they kill
tumor cells in all stages of the cell cycle and bind DNA through
the formation of intrastrand and interstrand cross-links, thereby
leading to inhibition of DNA synthesis and function.
The primary binding site is the
N7 position of guanine, but covalent interaction with the N3 position of adenine and O6 position of cytosine can also occur. In addition to targeting DNA, the platinum analogs have been shown to bind to both cytoplasmic and nuclear proteins, which may also
contribute to their cytotoxic and antitumor effects.
combination therapy of platinum analogs
The platinum complexes appear to synergize with certain other anticancer drugs,
including alkylating agents, fluoropyrimidines, and taxanes.
strucuture of cisplatin, oxiplatin and carboplatin
Cisplatin and carboplatin are divalent, inorganic, water
soluble platinum-containing complexes. Oxaliplatin is a tetravalent complex.(diaminocyclohexane analog)
chemistry and mechanism of action of platinum analogs
Cisplatin, carboplatin, and oxaliplatin enter cells by
an active Cu2+ transporter (CTR1).
Inside the cell, the chloride, cyclohexane, or oxalate
ligands of the three analogs are displaced by water
molecules, yielding a positively charged and highly
reactive molecule.
In the primary cytotoxic reaction, the aquated
species of the drug then reacts with nucleophilic sites
on DNA and proteins.
The activated platinum complexes can react with
electron-rich molecules, such as sulfhydryls, and
with various sites on DNA, forming both intrastrand
and interstrand cross-links.
The N-7 of guanine is a particularly reactive site,
leading to platinum cross-links between adjacent
guanines (GG intrastrand cross-links) on the same
DNA strand.
how cisplatin causes destruction
Cisplatin, among others, attacks mitochondria and
triggers the production of ROS, destroys lysosomes
inducing the release of lysosomal proteases and
degrades endoplasmic reticulum which results in the
deregulation of calcium storage and in the misfolded
proteins.
Beside the DNA in mitochondria, cisplatin attacks
other organelles by forming adducts with functional
groups on proteins, especially with the sulphur atom
in cysteine and methionine side chains.
combination therapy of cisplatin
Cisplatin, in combination with bleomycin, etoposide,
ifosfamide, or vinblastine, cures 90% of patients with
testicular cancer (Combination is effective to prevent
resistance).
broad spectrum of cisplatin
With paclitaxel, cisplatin or carboplatin induces complete
response in the majority of patients with carcinoma of the
ovary.
Cisplatin produces responses in cancers of the bladder, head
and neck, cervix, and endometrium; all forms of carcinoma of
the lung; anal and rectal carcinomas; and neoplasms of
childhood.
The drug also sensitizes cells to radiation therapy and control
of locally advanced lung, esophageal, and head and neck
tumors when given with irradiation.
comparison of carboplatin with cisplatin
Carboplatin and cisplatin are equally effective in the
treatment of ovarian cancer, non–small cell lung
cancer, and extensive-stage small cell lung cancer.
However, carboplatin may be less effective than
cisplatin in germ cell, head and neck, and esophageal
cancers.
