Thiarabine

Fact Sheet

What is Thiarabine?

Several nucleoside analogs are in routine clinical use for the treatment of cancer. Interest in the class of molecule remains high; three new nucleosides have received FDA approval with the past few years (cladribine, fludarabine, and gemcitabine). Nucleosides antimetabolites are effective in treating cancer because they are similar in structure to the natural nucleosides that are the building blocks of DNA and RNA. Cancer cells are ‘fooled’ into using these unnatural nucleosides for making DNA and/or RNA, resulting in chain termination and inhibition of DNA or RNA synthesis. Cell division is inhibited and ultimately tumor cell death occurs. Small changes in the structure of nucleosides can have a profound effect on the anticancer properties of these compounds, and there has been extensive research into nucleosides to produce compounds with improved activity.

Thiarabine is 4′-thio-beta-D-arabinofuranosylcytosine (4′-thio-ara-C). This molecule was developed by the Southern Research Institute and is licensed to Access Pharmaceuticals. The structure of thiarabine is similar to the structure of ara-C, a nucleoside used extensively in anticancer therapy. In thiarabine, the ring oxygen atom of ara-C is substituted by a sulfur atom.

 

Thiarabine Preclinical Studies

Thiarabine exhibited significant activity, including regressions or cures, in six tested leukemia or lymphoma cell lines. The compound produced better activity than ara-C or a fatty acid-modified ara-C (depot) analog in four of six tested models. Thiarabine also performed as well or better than clofarabine and gemcitabine in each of the models.

Unlike ara-C, thiarabine was found to be active in a wide variety of solid tumor xenograft models (14 different cell lines), including colorectal, lung, renal, prostate, breast and pancreatic tumors, mainly via intraperitoneal administration (one model was done iv). Thiarabine produced regressions or tumor-free survivors in about half of the models and exhibited better activity than gemcitabine or clofarabine in many models. Thiarabine activity was also better than that of paclitaxel or cisplatin in certain lung models. An increase in regression or cure rate over either compound alone was observed with combinations of thiarabine and cisplatin in lung tumors, thiarabine and irinotecan or clofarabine in colorectal tumors, and thiarabine plus clofarabine in a leukemia model.
This figure shows tumor growth inhibition of s.c. implanted CAKI-1 renal tumors in mice. Thiarabine was administered daily, 90mg/m2/dose, on days 14-22 (triangles) or 3 times a day at 30 mg/m2/dose, days 14-22 (squares) versus control (circles). The growth curves are only for mice with observable tumors. There were 4/6 cures in the group treated daily, and 2/6 in the group treated 3 times daily; 0/12 tumor-free survivors in the control group.

 
This figure shows tumor growth inhibition of s.c. implanted RL Lymphoma tumors by thiarabine and by several other nucleoside derivatives. All treatments are monotherapy, and the growth curves are only for mice with observable tumors.

 

Thiarabine Clinical Studies

Two phase 1 studies were conducted of thiarabine monotherapy in patients with solid tumors.

In the first phase 1 study, 26 patients with incurable advanced and/or metastatic solid tumors were enrolled. The protocol involved dose escalation, starting at 100 mg/m2 iv over 30 minutes on days 1 and 8, every three weeks. Patients were dosed at 200, 400, 500, and 600 mg/m2.

Out of 21 evaluable patients, 9 experienced stable disease (median duration 4.3 months, range 1.8-6.4 months).

Dose-limiting toxicities (DLTs) were observed at 400-600 mg/m2. Unlike previous observations with gemcitabine and ara-C (where the DLT is myelosupression; leucopenia and thrombocytopenia), there were no grade four toxicities and no hematological toxicities other than reversible, lymphopenia. Investigators concluded that the (Grade 3) dose-limiting toxicities were fatigue, rash, fever, seizure and lymphopenia.

A second solid tumor phase 1 trial was carried out to explore other schedules. The schedules were 200 mg/m2 via 60-minute IV infusion every 21 days, 5-minute bolus on same schedule, and 5-minute bolus weekly for 4 weeks starting with a dose of 100 mg/m2. Of the 27 evaluable patients, 7 patients (bladder cancer and mesothelioma) achieved disease stabilization (median 3.7 months, range 1.9-5.4). The main toxicity was fatigue, which appeared to be schedule independent.

Future Thiarabine Clinical Development

The excellent results seen for thiarabine in leukemia and lymphoma preclinical models and the lymphopenia observed in clinical studies provides a strong rationale for further investigation of thiarabine in leukemia and lymphoma patients. Access plans to initiate further thiarabine clinical studies in at least one of these patient populations in 2009.


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