來自海底的最新的抗乳房癌藥物 - Eribulin

The latest breast-cancer chemotherapy to hit the market is more than just a triumph for patients in desperate need of treatment. Approved by the US Food and Drug Administration on 15 November, the highly complex molecule Halaven (eribulin mesylate) is the product of nearly 25 years of struggle in the lab. It represents a hard-won victory for the total synthesis of natural products, a field of chemistry that, although still popular in academia, had gone out of fashion for many in the pharmaceutical industry.

Eribulin is a synthetic compound that mimics part of the structure of halichondrin B, a molecule found in the sea sponge Halichondria okadai. Researchers learned that halichondrin B has potent tumour-fighting activity shortly after its discovery in 1986. But it is present in very low concentrations, making it difficult to isolate. The compound also has a fiendishly complicated structure — at the time of its discovery, producing it from scratch was well beyond the abilities of chemists.

A few years later, however, organic chemist Yoshito Kishi of Harvard University in Cambridge, Massachusetts, eyed the halichondrin B structure and decided to take a crack at it. His team had little interest in its anticancer properties, he says. They were simply looking for a project to test a chemical reaction — the Nozaki–Hiyama–Kishi reaction — that could be used to build bonds between carbon atoms.

Kishi's team had set themselves an enormous challenge with halichondrin B. Natural products often contain carbon stereocentres, in which surrounding atoms can be arranged in two mirror-image configurations. "If you don't get the stereocentres set up perfectly, it generates a mixture" of different molecules that can be extremely troublesome to separate, says Ian Paterson, a chemist at the University of Cambridge, UK, who works on natural-product synthesis. Although two mirror-image forms of a molecule are indistinguishable for most chemical reactions, they can produce completely different biological effects.

Halichondrin B has a staggering 32 stereo-centres, meaning that there are 232 — more than 4 billion — possible forms, or isomers, of the molecule. "It's just ridiculous," says Robert Salomon, an organic chemist at Case Western Reserve University in Cleveland, Ohio, whose lab spent four years unsuccessfully trying to synthesize the compound in the early 1990s.

Nevertheless, Kishi's team succeeded. By the time he published a method for synthesizing the compound in 1992 (T. D. Aicher et al. J. Am. Chem. Soc. 114, 3162–3164; 1992), researchers at the Natural Products Branch of the US National Cancer Institute (NCI) in Frederick, Maryland, had discovered that halichondrin B fights cancer cells by inhibiting a protein component of the cytoskeleton — the internal latticework of rods and filaments that gives a cell its shape. That protein, called tubulin, is needed to support the rapid growth of cancer cells and is the target of several other cancer chemotherapies, including Taxol (paclitaxel).

Deep-sea drug
But Kishi's synthesis was practical for generating only small quantities of halichondrin B, unlikely to be enough to usher the compound through preclinical and then clinical testing, says David Newman, now chief of the NCI's Natural Products Branch. Newman decided that he would simply isolate the compound from natural samples. So he headed for the sea to hunt for the prized compound.

Newman and his team collected more than one tonne of Lissodendoryx, another type of sponge containing halichondrin B, from the deep waters off New Zealand. He also teamed up with researchers to grow more of the sponges, flying seaplanes out to remote aquatic farms where the sponges grew attached to lines dangling 40 metres beneath buoys. The reward for his efforts: just 300 milligrams of halichondrin B, the equivalent of a few grains of rice. "My hair turned white as a result of halichondrin B," he jokes.

Meanwhile, Tokyo's Eisai Pharmaceuticals had licensed the patent on Kishi's method and began synthesizing hundreds of analogues of the compound. Newman's haul from New Zealand was just enough to conduct comparative studies with some of these analogues. One of them, eribulin, is more potent than halichondrin B yet also substantially smaller and easier to make. But it still has 19 stereocentres (see structure), and production of eribulin on a commercial scale seemed unfathomable.

Eisai says that eribulin takes 62 steps to synthesize — a remarkably long process for a marketable drug. The company was initially apprehensive about the project, says Kishi. But once the phase I study results had shown that the drug was safe — and revealed hints of clinical efficacy — "all the reservations disappeared", he says.

Further clinical trials showed that eribulin extends the lifespan of patients with late-stage breast cancer by an average of 2.5 months in those who are not benefiting from other chemotherapies such as Taxol, also a natural-product derivative. Analysts suggest that eribulin could command a US$1-billion market if it is approved for treatment of other cancers.

Few other pharmaceutical companies have been willing to bet on complex natural products. During the 1990s, many largely abandoned natural-product chemistry, focusing more on screening large libraries of synthetic chemicals for drug candidates, says Michael Jirousek, who once worked on halichondrin B synthesis and is now chief scientific officer and co-founder of Catabasis, a biotechnology company in Cambridge, Massachusetts. "Screening natural products and isolating the active ingredients is becoming a lost art," he says.

Proponents of total synthesis point to eribulin as proof that their approach, albeit arduous, can be highly successful. Phil Baran, a synthetic chemist at the Scripps Research Institute in La Jolla, California, says that more young investigators are entering the field and that improvements in chemical techniques are making it possible to synthesize additional complex molecules by commercially viable routes. "As advances in organic chemistry become greater and greater," he says, "I think we're going to see a lot more complex compounds being pursued by companies."

英國《自然》雜誌的新聞評論 http://www.nature.com/news/2010/101130/full/468608a.html


美國食品和藥品監督管理局 2010年11月15日批準Halaven(eribulin mesylate)治療轉移乳癌患者對其晚期疾病曾接受至少2種既往化療方案。

根據美國國家癌症研究所，乳癌是婦女中第二位領先的癌死亡相關原因。本年度，估計207,090婦女將被診斷有乳癌，而39,840婦女將死於該疾病。

Halaven是來自海海綿Halichondria okadai化療活性化合物的一種合成形式。這種可注射的治療是一種微管抑製劑，被認為通過抑製癌細胞生長起作用。接受Halaven前，患者應曾對早期或晚期乳癌接受既往基於蒽環類[anthracycline]-和紫杉烷類[taxane]-化療。

在一項762例轉移乳癌婦女對晚期疾病曾接受至少2種既往化療方案的單獨研究中確定Halaven的安全性和有效性。患者被隨機賦予接受治療用或者Halaven或被他們的腫瘤學家選擇的不同的一種單藥治療。

研究被設計成測量當這種治療開始直至患者死亡時間的長度(總生存)。接受Halaven患者中位總生存是13.1個月，與之比較接受某種單藥治療為10.6個月。

FDA的藥物評價和研究中心所屬腫瘤藥物產品室主任Richard Pazdur, M.D.,說：“對早已接受其它治療有侵襲型晚期乳癌婦女，治療選擇很有限。”“Halaven顯示明確的生存效益和對婦女是一種重要的新選擇。”

用Halaven治療婦女報道的最常見副作用包括感染，中性白細胞減少(中性粒細胞減少)，貧血，白血細胞數減少(白細胞減少症)，毛發脫落(脫發)，疲勞，惡心，軟弱(虛弱), 神經損傷(周圍神經病變)，和便秘。

FDA-批準用於治療晚期，難治性乳癌的其它治療包括Xeloda(卡培他濱[capecitabine])對紫杉醇[paclitaxel]和蒽環類-含化療耐藥乳癌患者；Ixempra(伊沙匹隆[ixabepilone])對蒽環類，紫杉烷類和Xeloda失敗後晚期疾病患者；和Ixempra加Xeloda對基於蒽環類-和紫杉烷類化療失敗後晚期疾病患者。。。