Gemcitabine

Medical uses

Gemcitabine is used in various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. It is being investigated for use in esophageal cancer, and is used experimentally in lymphomas and various other tumor types.

Gemcitabine is administered by the intravenous route, since it is extensively metabolized by the gastrointestinal tract.

Bladder cancer

Gemcitabine became first line treatment for bladder cancer Stage 4 with metastases in combination with cisplatin after a study in 2000 with 405 patients showed similar efficacy but less toxicity compared to the former MVAC regimen. This new CG-regimen involves taking cisplatin on day 2 and taking gemcitabine on days 1, 8, and 15.

Ovarian cancer

In July 2006 the FDA approved gemcitabine for use with carboplatin in the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based (e.g., carboplatin or cisplatin) therapy. Neutropenia was the most commonly reported adverse effect (90% of patients). Other serious adverse effects were mostly hematologic.

Lung cancer

GemCarbo chemotherapy, consisting of a combination of gemcitabine and carboplatin, is used to treat several different types of cancer, but is most commonly used to treat lung cancer. GemCarbo chemotherapy is usually given as a day patient treatment, involving a blood test the day before, and the drugs are given by an infusion. The GemCarbo regimen is given as a 21-day cycle and on the first day of treatment the patient is given both the gemcitabine and carboplatin. On the same day of the following week (day eight) there is a drip of gemcitabine only. There then follows a rest period of two weeks which completes one cycle of chemotherapy. The next cycle of treatment is given after a rest period, which will be three weeks after the first injection. Usually 4–6 cycles of treatment are given over a period of 3–4 months and this makes up a course of treatment.

Pharmacology

Chemically gemcitabine is a nucleoside analog in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms.

As with fluorouracil and other analogues of pyrimidines, the triphosphate analogue of gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumor growth, as only one additional nucleoside can be attached to the "faulty" nucleoside, resulting in apoptosis.

Another target of gemcitabine is the enzyme ribonucleotide reductase (RNR). The diphosphate analogue binds to RNR active site and inactivates the enzyme irreversibly. Once RNR is inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair, and cell apoptosis is induced.

History

Gemcitabine was first synthesized in Larry Hertel's lab at Eli Lilly during the early 1980s. It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro. It was first licensed in the UK in 1995.

Pancreatic cancer

A study reported in the Journal of the American Medical Association in 2007 suggested that gemcitabine showed benefit in patients with pancreatic cancer who were felt to have successful tumor resections.

The addition of capecitabine to gemcitabine was studied in the ESPAC-4 trial and found beneficial.

Other

Gemcitabine was also investigated for advanced cancer of the biliary tract and gallbladder and was found to have a modest effect on the tumor when combined with cisplatin (NEJM 2010).

As with many nucleoside analogues, gemcitabine may show antiviral activity as well as anti-cancer properties. Preliminary in vitro and mouse studies have shown it to be effective against enteroviruses such as coxsackievirus and poliovirus, as well as showing weaker activity against rhinoviruses, influenza and HIV, though it remains unclear whether gemcitabine is safe and effective enough in these applications to be developed for medical use as an antiviral agent.