Future directions for clinical research with CPT-11 (irinotecan)

Our plain-English summary of Future directions for clinical research with CPT-11 (irinotecan), by D. von Hoff (European Journal of Cancer, 1996).

The study

• Author: D. von Hoff
• Journal: European Journal of Cancer
• Published: 1996;32A Suppl 3:S9-12
• Type of article: Review
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

CPT-11 is a new agent with a unique mechanism of action, namely the inhibition of topoisomerase I. An examination of data from the laboratory reveals several leads which should be pursued in the clinic. A dose-response effect for CPT-11 activity has been noted in the human tumour cloning assay. CPT-11 has activity against breast and mesothelioma colony-forming units in a human tumour cloning assay, and has in vivo activity against a number of paediatric malignancies. Promising combinations in preclinical in vivo models include CPT-11/mitomycin C and CPT-11/cytosine arabinoside. There is incomplete cross-resistance among topoisomerase I inhibitors, suggesting that combinations of topoisomerase I inhibitors should be investigated. Several natural products have been identified which have potential to decrease CPT-11-induced diarrhoea. The level of carboxylesterase in a patient's tumour appears to be related to the in vitro activity of CPT-11, suggesting that measurement of carboxylesterase in a patient's tumour could be used to identify patients who are most likely to respond to treatment with CPT-11. These preclinical findings suggest substantial further clinical potential for CPT-11 in terms of decreased CPT-11-induced diarrhoea as well as increased antitumour activity, which should be explored in phase I and II studies.

In plain English

This article was a review of laboratory (preclinical) findings on the anticancer drug CPT-11 (irinotecan), written by a researcher at the Institute for Drug Development in San Antonio, Texas. It set out leads the author believed should be tested in clinical trials. It was not a study of asbestos exposure. In the author's group's human tumour cloning assay, tumour specimens taken from patients responded more often at higher drug concentrations: 8/124 (6%) at 0.3, 20/135 (15%) at 1.5 and 41/125 (33%) at 3.0 micrograms per ml. The article reported responses in six of 13 breast cancer specimens and in 4/12 mesothelioma specimens. It did not say where in the body the mesotheliomas arose. In 9 of 24 specimens (38%), CPT-11 and a related drug, topotecan, were not cross-resistant. The review also cited work by Chen and colleagues that listed mesothelioma among the tumour types with the highest levels of carboxylesterase, an enzyme that converts CPT-11 into its active form. The author recommended phase II trials in breast cancer and mesothelioma, and noted that the number of sarcoma specimens tested was small.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review (narrative summary of preclinical laboratory and animal findings, including the author's group's tumour cloning assay data, with recommendations for clinical trials)
• Who was studied: Tumour specimens taken directly from patients and tested in a human tumour cloning assay by the author's group in San Antonio, Texas (for example 24 specimens in the cross-resistance test, 12 mesothelioma specimens in the tumour-type table). The review also discusses other investigators' patient trials and mouse xenograft studies.
• Exposure: Not an asbestos study. The exposure studied was the anticancer drug CPT-11 (irinotecan), a topoisomerase I inhibitor, applied to tumour specimens in the laboratory (for example 0.3, 1.5 and 3.0 micrograms per ml; 1.0 microgram per ml for 1 hour in the topotecan comparison).
• Main results:
  • Concentration-response in the human tumour cloning assay: 8/124 (6%) of evaluable specimens responded at 0.3 micrograms per ml, 20/135 (15%) at 1.5, and 41/125 (33%) at 3.0
  • Breast cancer specimens: six in vitro responses in 13 specimens
  • Mesothelioma specimens: responses in 4 of 12 specimens (type or site of mesothelioma not stated)
  • Non-cross-resistance between CPT-11 and topotecan was seen in 9 of 24 patient tumour specimens (38%)
  • Citing Chen and colleagues (not this author's own data), the review reported that mesothelioma was among the tumour types with the highest carboxylesterase activity in 179 tumours, and that tumours with the highest levels were the most sensitive to CPT-11 in the cloning assay
• The authors' conclusion: The author concluded that much preclinical information on CPT-11 remains to be pursued in well-designed clinical trials, and recommended phase II trials in patients with breast cancer and with mesothelioma.
• Limitations the authors state:
  • The number of sarcoma specimens tested was small
  • The relationship between topoisomerase I levels in a patient's tumour and that tumour's response to CPT-11 had not been explored prospectively

Topics

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Mesothelioma, Mitomycin C.

Related studies

• Docetaxel and irinotecan (CPT-11) in the treatment of malignant pleural mesothelioma--a feasibility study — A. Knuuttila, T. Ollikainen, et al. (2000)
• Small cell carcinoma presenting with massive pleural spread mimicking malignant pleural mesothelioma — T. Takeda, M. Saitoh, et al. (2014)
• Cisplatin and irinotecan (CPT-11) for peritoneal mesothelioma — D.T. Le, M. Deavers, et al. (2003)
• In vitro sensitivity of normal human mesothelial and malignant mesothelioma cell lines to four new chemotherapeutic agents — T. Ollikainen, A. Knuuttila, et al. (2000)
• Raltitrexed: current clinical status and future directions — E. Van Cutsem, D. Cunningham, et al. (2002)
• The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors — B.S. Choi, D.B. Alberti, et al. (2010)

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