Plant alkaloids pharmacology
Plant alkaloids are anticancer agents derived from plants. These drugs act specifically by blocking the ability of a cancer cell to divide and become two cells. Although they act throughout the cell cycle, some are more effective during the S- and M- phases, making these drugs cell cycle specific.
VinblastineVinblastine is an alkaloid derived from the periwinkle plant vinca rosea.
Its mechanism of action involves inhibition of tubulin polymerization, which disrupts the 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.
Toxicity includes nausea and vomiting,
bone marrow suppression, and alopecia. This agent is also a potent
vesicant, and care must be taken in its administration.
It has clinical activity in the treatment of hodgkin's disease, non-hodgkin's lymphomas, breast cancer, and germ cell cancer.
is an alkaloid derivative of vinca rosea and is closely related in
structure to vinblastine. Its mechanism of action is considered to be
identical to that of vinblastine in that it functions as a mitotic
spindle poison leading to the arrest of cells in the m phase of the cell
cycle. Despite these similarities to vinblastine, vincristine has a
strikingly different spectrum of clinical activity and toxicity.
Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children.
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.
The main dose-limiting toxicity is
neurotoxicity, usually expressed as a peripheral sensory neuropathy,
although autonomic nervous system dysfunction—with orthostatic
hypotension, sphincter problems, and paralytic ileus—cranial nerve
palsies, ataxia, seizures, and coma have been observed.
myelosuppression can occur, it is generally milder and much less
significant than with vinblastine. The other potential side effect that
can develop is the syndrome of inappropriate secretion of antidiuretic
Vinorelbine is a
semisynthetic vinca alkaloid whose mechanism of action is identical to
that of vinblastine and vincristine, ie, inhibition of mitosis of cells
in the m phase through inhibition of tubulin polymerization. This agent
has activity in non-small cell lung cancer and in breast cancer.
Myelosuppression with neutropenia is the dose-limiting toxicity, but
nausea and vomiting, transient elevations in liver function tests,
vp-16 (etoposide) and a related drug, vm-26 (teniposide), are
semisynthetic derivatives of podophyllotoxin, which is extracted from
the mayapple root (podophyllum peltatum). Both an intravenous and an
oral formulation of etoposide are approved for clinical use in the usa.
and teniposide are similar in chemical structure and in their
effects—they block cell division in the late s-g2 phase of the cell
cycle. Their primary mode of action involves inhibition of topoisomerase
ii, which results in dna damage through strand breakage induced by the
formation of a ternary complex of drug, dna, and enzyme.
drugs are water-insoluble and have to be formulated in a cremophor
vehicle for clinical use. These agents are administered via the
intravenous route and are rapidly and widely distributed throughout the
body except for the brain. Up to 90–95% of drug is protein-bound, mainly
Dose reduction is required in the setting of
renal dysfunction. 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 and as high-dose therapy in the transplant
setting for breast cancer and lymphomas. Teniposide use is limited
mainly to acute lymphoblastic leukemia.
camptothecins are natural products that are derived from the
camptotheca acuminata tree, and they inhibit the activity of
topoisomerase i, the key enzyme responsible for cutting and religating
single dna strands. Inhibition of the enzyme results in dna damage.
is indicated in the treatment of advanced ovarian cancer as second-line
therapy following initial treatment with platinum-based chemotherapy.
It is also approved as second-line therapy of small cell lung cancer.
The main route of elimination is renal excretion, and dosage must be
adjusted in patients with renal impairment.
Irinotecan is a
prodrug that is converted mainly in the liver by the carboxylesterase
enzyme to the sn-38 metabolite, which is a potent inhibitor of
topoisomerase i. In contrast to topotecan, irinotecan and sn-38 are
mainly eliminated in bile and feces, and dose reduction is required in
the setting of liver dysfunction. Irinotecan was originally approved as
second-line monotherapy in patients with metastatic colorectal cancer
who had failed fluorouracil-based therapy.
It is also approved as first-line therapy when used in combination with 5-fluorouracil and leucovorin.
and diarrhea are the two most common adverse events. There are two
forms of diarrhea: an early form that occurs within 24 hours after
administration and is thought to be a cholinergic event effectively
treated with atropine, and a late form that usually occurs 2–10 days
after treatment. Late diarrhea can be severe, leading to significant
electrolyte imbalance and dehydration in some cases.
is an alkaloid ester derived from the pacific yew (taxus brevifolia)
and the european yew (taxus baccata). The drug functions as a mitotic
spindle poison through high-affinity binding to microtubules with the
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.
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.
reactions may be observed in up to 5% of patients, but the incidence
can be reduced by premedication with dexamethasone, diphenhydramine, and
an h2 blocker.
A novel albumin-bound paclitaxel formulation (Abraxane) has recently been approved for use in metastatic breast cancer. In contrast to paclitaxel, this formulation is not associated with hypersensitivity reactions, and premedication to prevent such reactions is not required. Moreover, this agent has significantly reduced myelosuppressive effects compared with paclitaxel, and the neurotoxicity that results appears to be more readily reversible than is typically observed with paclitaxel.
Docetaxel is a semisynthetic
taxane derived from the European yew tree. Its mechanism of action,
metabolism, and elimination are identical to those of paclitaxel. It is
approved for use as second-line therapy in advanced breast cancer and
non-small cell lung cancer, and it also has major activity in head and
neck cancer, small cell lung cancer, gastric cancer, advanced
platinum-refractory ovarian cancer, and bladder cancer.
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