Topoisomerase Inhibitors Promising in Cancer, in Colorectal Tumors Especially

Topoisomerase Inhibitors Promising in Cancer, in Colorectal Tumors Especially

by David W. Sharp

WHAT'S HOT IN MEDICINE

Rank	Paper	Citations This Period Nov-Dec 01	Rank Last Period Sep/Oct 01
1	C. Bombardier, et al., "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis," New Engl. J. Med., New Engl. J. Med., 343(21):1520-8, 23 November 2000. [14 institutions worldwide] *375PR	50	2
2	F.E. Silverstein, et al., "Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial," JAMA-J. Amer. Med. Assn., 284(10):1247-55, 13 September 2000. [12 U.S. institutions] *350WL	49	5
3	S. Yusuf, et al., "Effects of angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients," New Eng. J. Med., 342(3):145-53, 20 January 2000. [Hamilton Gen. Hosp., Ont., Canada] *275ZT	37	1
4	P.M. Ridker, et al., "C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women," New Engl. J. Med., 342(12):836-43, 23 March 2000. [Brigham & Women's Hosp., Boston, MA; Harvard U. Sch. Med., Boston; Children's Hosp., Boston] *296FU	32	3
5	G.R. Bernard, et al., "Efficacy and safety of recombinant human activated protein C for severe sepsis," New Engl. J. Med., 344(10):699-709, 8 March 2001. [9 institutions worldwide] *408AX	30	8
6	B.J. Druker, et al. "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia," New Engl. J. Med., 344(14):5 April 2001. [Oregon Hlth. Sci. U., Portland; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ; U. Calif., Los Angeles] *417XH	29	†
7	A. Kugler, et al., "Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids," Nature Medicine, 6(3):332-6, March 2000. [U. Gottingen, Germany; U. Tubingen, Germany; Humboldt U., Berlin, Germany] *288TL	31
8	B.J. Druker, et al., "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome," New Engl. J. Med., 344(14):1038-42, 5 April 2001. [Oregon Hlth. Sci. U., Portland; Univ. Calif., Los Angeles; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ] *417XH	28	†
9	A.M.J. Shapiro, et al., "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen," New Engl. J. Med., 343(4):230-8, 27 July 2000. [U. Alberta, Edmonton, Canada] 337QC	25	6
10	G.G. Schwartz, et al., "Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial," JAMA-J. Amer. Med. Assn., 285(13):1711-8, 4 April 2001. [13 institutions worldwide] *415FR	24	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

n this issue, as a consequence of ISI’s recent change from one method of Hot Papers extraction to another, Science Watch readers (and columnists) are being exposed to roughly the same citation window as last time. Let us take advantage of that and dip below the "Top Ten" to look at a new class of drugs that is beginning to make an impact in cancer chemotherapy.

DNA topoisomerases ensure that as DNA divides it does not come under too much torsional stress. Agents that inhibit this mechanism will act against rapidly dividing cells. Ciprofloxacin, in the news last year because of the U.S. anthrax scare, attacks the topoisomerase type II (or gyrase) found in bacteria. Cancer specialists are interested in inhibitors of type I topoisomerases (or nicking-closing enzymes), a new drug class stemming from initial work on camptothecin, from the Chinese tree Camptotheca acuminata. The drug most studied clinically is irinotecan; others are topotecan, lurtotecan, and exatecan. Creeping in at #12 is a European collaborative randomized trial of fluorouracil, formerly the standard chemotherapy for advanced (metastatic) colorectal cancer, with or without irinotecan (J.Y. Douillard, et al., Lancet, 355[9209]:1041-9, 25 March 2000, with 20 citations this period).

The prognosis for patients whose cancers have already migrated, usually to the liver, is not good, and it would be foolish to expect spectacular results. One of the several reported advantages for the new drug combination was statistically significantly increased survival times, but median survival was only about 100 days longer when irinotecan was added. A similar result was recorded later in the same year by Leonard B. Saltz and colleagues in the Irinotecan Study Group (L.B. Saltz, et al., New Engl. J. Med., 343[13]:905-14, 28 September 2000, cited 12 times this period). Here the median overall survival was 12.6 months with the standard therapy and 14.8 months with the irinotecan combination.

The combination of irinotecan with fluorouracil (plus leucovorin, or folinic acid, a B vitamin that facilitates binding of fluorouracil to its primary target enzyme) was approved in the United States just over two years ago. This "Saltz regimen" has been widely welcomed, so the announcement in April, 2001, that two further trials of this regimen were to be suspended on safety grounds came as a disappointment. However, the trials were soon reopened, with dose reductions in the one still recruiting patients.

Saltz explains the safety issue for Science Watch: "As presented to the Oncology Drug Advisory Committee of the Food and Drug Administration on December 6, 2001, there was not an increase in deaths relative to either prior studies with the regimen or prior colorectal studies." A new measurement, 60-day all-cause mortality, had been applied to the new studies but not the old ones. "When 60-day all-cause mortality was applied consistently," Saltz notes, "the death rates are, if anything, lower than had been reported previously."

Saltz, from the Memorial Sloan-Kettering Cancer Center, New York, NY, included the current status of irinotecan in his recent joint review in one of The Lancet’s sister journals (K.D. Holen, L.B. Saltz, Lancet Oncology, 2[5]:290-7, 1 May 2001), a paper that will have gone to press before last year’s safety concerns. When put together, the U.S. and European trials reveal "highly statistically significant (p = 0.003) improvements in response rate, progression-free survival, and overall survival" with the new drug combination.

Read an interview with Dr. Salim Yusuf in in cites.com. Dr. Yusuf talks about the Heart Outcomes Prevention Evaluation (HOPE) Study. According to data from ISI Essential Science Indicators Web product, Dr. Yusuf's paper "Effects of angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients," has been cited a total of 236 times to date, placing it among the top five papers published in the past two years in the field of Clinical Medicine.

Mr. David W. Sharp, M.A. (Cambridge), was deputy editor of The Lancet,
London, U.K., from 1976 to May, 2001; he is currently a contributing editor to that journal.

Science Watch^®, May/June 2002, Vol. 13, No. 3
Citing URL: http://www.sciencewatch.com/may-june2002/sw_may-june2002_page5.htm