Vinca Alkaloids

Four major vinca alkaloids are in clinical use for cancer: vinblastine, vinorelbine, vincristine, and vindesine.

These are sometimes called monoterpenoid indole alkaloids in the scientific literature.  All vinca alkaloids are administered intravenously (IV). They are eventually metabolized by the liver and excreted.

Inside the Malignant Cells

The vinca alkaloids are cytotoxics – they halt the division of cells and cause cell death. During cell division, vinca alkaloid molecules bind to the building blocks of a protein called tubulin, inhibiting its formation. The drugs work during the M-phase of cell reproduction. Tubulin protein normally works in cells to create “spindle fibers,” (also called microtubules). These microtubules provide cells with both the structure and flexibility they need to divide and replicate. Without microtubules, cells cannot divide. The vinca alkaloid’s mechanism in a nutshell: by occupying tubulin’s building block structure, vinca alkaloids prevent cancer cells from successfully dividing.

Vinblastine inhibits angiogenesis, or the process by which new blood vessels grow from pre-existing ones. Angiogenesis is an essential step in a tumor’s transition to malignancy. Vinblastine is most often applied to treat Hodgkin’s disease, non-Hodgkin’s lymphoma, breast cancer, and germ cell tumors. Side effects of vinblastine include: toxicity to white blood cells, nausea, vomiting, constipation, dyspnea, chest or tumor pain, wheezing, and fever. Vinblastine sometimes causes antidiuretic hormone secretion and angina.

Vinorelbine acts the same way as vinblastine. Vinorelbine has exhibited significant antitumor activity in patients with breast cancer and antiproliferation effects on osteosarcoma (bone tumor cells). Furthermore, vinorelbine has been shown to decrease the stability of lipid bilayer membranes (like those of a cell’s). Vinorelbine’s side effects include: decreased resistance to infection, bruising or bleeding, anemia, constipation, diarrhea, nausea, numbness or tingling in the hands and feet, fatigue (also called peripheral neuropathy), and inflammation at the injection site. Less common side effects include hair loss and allergic reaction.

Vincristine’s inhibition of microtubule formation is especially powerful. The reason for this comes from the fact that tubulin protein is dynamic. Its long chain of building blocks is always growing in some places and breaking in others. The less contiguous parts of a tubulin molecule have pieces only two building blocks long, called dimers. Vincristine has a high affinity for tubulin dimers, and the reaction between vincristine and the dimers is rapidly reversible. That means a vincristine molecule will attach to a dimer at one site, break off, and then reattach at another site. This keeps two sites per dimer “poisoned” and unable to reassemble into the protein. So vincristine’s ability to destabilize tubulin is especially good.

Vincristine is FDA approved to treat acute leukemia, rhabdomyosarcoma, neuroblastoma, Wilm’s tumor, Hodgkin’s disease, and other lymphomas. Vincristine’s most common side effects are: peripheral neuropathy, suppression of bone marrow activity, constipation, nervous system toxicity, nausea, and vomiting.

Vindesine has a serum half-life of only 24 hours, but similar effects (intended and side) to that of vinblastine. Vindesine is administered at a dose of 3 milligrams per square meter of body surface. The drug is applied to treat melanoma, lung cancers, and (combined with other drugs) uterine cancers. Additional side effects from vindesine include: anemia, blood cell toxicity, fatigue, tingling or pricking sensations in the skin, and skin toxicity.

vinca alkaloid mechanism

Nature’s Binary

Interesting thing about the periwinkle – although these compounds are derived from the leaves, they do not exist in significant quantities inside the plant while the plant is alive.  The plants do contain precursor alkaloids vindoline and catharanthine.  The catharanthine is in the waxy coating of the leaves.  When the leaves are broken – say by an animal looking for food – an opportunity is formed for mixing of the catharanthine and vindoline and for synthesis of the chemicals oncologists find useful in fighting cancer.  It is not known why evolution resulted in segregation of the two precursors but it might be because vinblastine, etc have toxic effects on the periwinkle plant.  In a somewhat analogous set up, the US army stocks binary chemical weapons – weapons that don’t become poisonous until two constituents and produce a chemical reaction on the battlefield.

Clinical Use

The vinca alkaloids are a subset of drugs derived from the Madagascar periwinkle plant. They were discovered in the 1950’s by Canadian scientists, Robert Noble and Charles Beer. Vinca alkaloids have been used to treat high blood pressure, and the drugs have even been used as disinfectants. The leaves of the periwinkle plant can be used to make a tea and it was once thought this tea would have a benefit for people with diabetes. Scientific investigation did not bear out this benefit.

Information on the exact usage rates of Vinca alkaloid drugs is scant, but sales figures show decreases for all of the cytotoxics used to treat cancer. In 2005, cytotoxics represented the majority of the Top 20 Cancer Therapeutics, according to datamonitor.com. This was due to cytotoxics’ long history in oncology and their key roles in current treatment. As of 2006, however, another type of drug has started to overtake the market. That drug type is called a molecular targeted therapy. Molecular targeted therapies were the leading class of cancer treatment of the Top 20 in Australia, with sales of $320 million in 2008. The molecular targeted therapy class has been most responsible for overall growth experienced by the oncology market between 2005 and 2008. One reason for this is that molecular targeted therapies lack the generic competition endured by cytotoxics like the vinca alkaloids. So while the vinca alkaloids are no longer in the highest selling class of cancer drugs, they are still in a class expected to generate revenues of $200 million over the next ten years when combined with the revenues generated by a third cancer drug class, the antihormonal treatments (bionity.com).

Overall, vinca alkaloids are in the second most-used class of cancer drugs but sales are expected to decline. Nonetheless, vinca alkaloids will remain among the fundamental cancer therapies. Research for new vinca alkaloid applications is ongoing.

Vinblastine

Other generic names:
Forumla:
Vincaleukoblastine C46H58N4O9
Trade names
Class (action)
Class (chemical)
Antimicrotubule Alkaloid (Vinca)
Administration
Intravenous
Notes
A mitotic inhibitor

Vinorelbine

Other generic names:
Forumla:
C45H54N4O8
Trade names
Navelbine
Class (action)
Class (chemical)
Mitotic inhibitor Alkaloid (Vinca)
Administration
Intravenous and (rarely) oral
Notes
A mitotic inhibitor

Vincristine

Other generic names:
Forumla:
Leurocristine C46H56N4O10
Trade names
Oncovin
Class (action)
Class (chemical)
Mitotic inhibitor Alkaloid (Vinca)
Administration
Intravenous
Notes
A mitotic inhibitor

Vindesine

Other generic names:
Forumla:
C43H55N5O7
Trade names
Class (action)
Class (chemical)
Mitotic inhibitor Alkaloid (Vinca)
Administration
Intravenous
Notes
A mitotic inhibitor