An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma.

Ohno, Ryuzo; Okada, Kōsuke; Masaoka, T; Kuramoto, Atsushi; Arima, Toshiharu; Yoshida, Yasushi; Ariyoshi, Hideo; Ichimaru, Michito; Sakai, Yoshinori; Oguro, M

doi:10.1200/jco.1990.8.11.1907

Cited by 205 publications

(61 citation statements)

References 9 publications

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“…Irinotecan (CPT-11) is a water-soluble camptothecin derivative that targets DNA topoisomerase I. CPT-11 has shown a strong anti-tumour activity as a single agent against a broad spectrum of experimental tumours (Kunimoto et al, 1987;Matsuzaki et al, 1988) as well as against various human malignancies including lung cancer (Ohno et al, 1990;Negoro et al, 1991b;Tacheuchi et al, 1991;Fukuoka et al, 1992; Masuda et al, 1992a;Shimada et al, 1993).…”

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A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer

Masuda

Fukuoka²,

Fujita³

et al. 1998

Br J Cancer

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Summary A phase trial of the combination of irinotecan (CPT-11) with cisplatin in advanced non-small cell lung cancer (NSCLC) showed a very promising response rate of 54% in previously untreated NSCLC patients. This study was conducted to confirm the activity and toxicities of CPT-11 and cisplatin combination for previously untreated NSCLC in a multi-institutional phase 11 study. Seventy patients with stage IIIB or IV NSCLC received CPT-11 60 mg m-2 intravenously (IV) on days 1, 8 and 15, and cisplatin 80 mg m-2 (IV) on day 1 every 4 weeks. Assessments were made of response, survival and toxicities. Sixty-nine were eligible, and evaluable for toxicities and survival, and 64 patients evaluable for response. Thirty-three patients (52%; 95% confidence interval 39-64%) achieved an objective response, with one complete response (2%) and 32 partial responses (50%). The median duration of response was 19 weeks and the overall median survival time was 44 weeks. The 1-year survival rate was 33%. The major toxic effects were leucopenia and diarrhoea. Grade 3 or 4 leucopenia, neutropenia, and diarrhoea occurred in 32 patients (46%), 53 patients (80%), and 13 patients (19%) respectively. A combination of CPT-11 and cisplatin is very effective against non-small-cell lung cancer with acceptable toxicities.

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A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer

Masuda

Fukuoka²,

Fujita³

et al. 1998

Br J Cancer

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“…Irinotecan has shown a good response in patients with relapsed and/or refractory malignant lymphoma (4)(5)(6). With regard to therapeutic efficacy of irinotecan in patients CPT-1 1 and Hodgkin's Lymphoma with Hodgkin's lymphoma, there is little information.…”

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“…Several clinical studies have shown that irinotecan has beneficial effects in patients with malignant lymphoma, especially relapsed and/or refractory nonHodgkin's lymphoma (4)(5)(6). However, the dose and schedule are still controversial.…”

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Successful Salvage Therapy of Irinotecan for Relapsed Hodgkin's Lymphoma.

et al. 2002

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A 30-year-old man, whohad a repeated history of relapsed Hodgkin's lymphoma over 7 years, developed bilateral pleural effusion and chest wall involvement. He was treated with weekly irinotecan hydrochloride (CPT-ll ; 80 mg/m2/week). Partial response was observed after two cycles of irinotecan. Neutropenia and diarrhea were tolerable. This case demonstrated that irinotecan has a therapeutic effect in patients with relapsed Hodgkin's lymphoma. (Internal Medicine 41 : 648-650, 2002)

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“…Fig. 1A), a CM-Dex-PA adduct of the antineoplastic agent, 2,3,9,12,4′:6,7]The carboxymethylated polyalcohol is covalently bonded to the DX-8951 moiety via a tetrapeptidyl spacer (Gly-Gly-Phe-Gly, GGFG). DX-8951f (Fig.…”

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DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

Kumazawa¹,

Ochi²

2004

Cancer Science

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he effect of current therapeutic agents appears when the agent acts on the target organ in the body. Since drug molecules that are distributed to organs that are not targeted may cause side effects, treatment is generally performed using a dose at which efficacy is obtained without unacceptable side effects. However, most antitumor chemotherapeutic agents show clinical effects only at doses that cause side effects such as digestive toxicity and myelosuppression. Therefore, in the development of new antitumor chemotherapeutic agents, it is important to discover compounds having a stronger antitumor effect and weaker toxicity compared with current antitumor chemotherapeutic agents. For example, CPT-11 was found to exhibit higher antitumor activity with less toxicity than camptothecin (CPT) and showed promising activity in clinical evaluation.1-8) However, it causes side effects such as severe watery diarrhea and there are marked inter-patient variations in both its effects and toxicity. 7, 9, 10) To obtain a more effective analogue with a lower toxicity, DX-8951f was designed.11) DX8951f is the most active inhibitor of topo I and tumor growth both in vitro and in vivo among the currently available CPT derivatives. [12][13][14] However, even with DX-8951f, there is no apparent increase in the selectivity to tumor tissue versus normal tissue and the half-life of the compound is relatively short (t 1/2 of 0.3 h mice). 15)The ideal antitumor drug would have high antitumor activity but no toxicity, i.e., it would be a compound for which efficacy and side effects are completely separate, but it is difficult to achieve this with low-molecular compounds, as the history of antitumor chemotherapeutics shows. Various approaches for superior targeting of antitumor compounds have been investigated by many researchers, and there have been trials of macromolecular pro-drugs. 16,17) Based on the results obtained from examinations of macromolecular conjugates using doxorubicin in DDS Institute, Ltd., we started to study drug delivery using a macromolecular carrier based on a DX-8951-conjugate, in order to enhance the antitumor effect and to reduce the hematological toxicity of DX-8951f.A novel macromolecular carrier system, based on the wellknown enhanced permeability and retention (EPR) effect, 18) was designed to target DX-8951 to tumors and to provide sustained release of DX-8951 in tumors. We conducted extensive optimization studies of the peptidyl spacer, molecular weight of the carrier, DX-8951 content and degree of carboxymenthylation.19) DE-310 is composed of DX-8951 and a biodegradable carrier, carboxymethyldextran polyalcohol (CM-Dex-PA), which are covalently linked by a peptidyl spacer (Gly-Gly-PheGly, GGFG).19) It has an average molecular weight of 340,000 (DX-8951 content: less than 8%, degree of carboxymethylation: ca. 0.3-0.4 per sugar residue). 19) In the present study, we examined the therapeutic efficacy of DE-310 against a variety of human and murine tumors in mice. Materials and MethodsCompounds. Fig. 1A), ...

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An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma.

Cited by 205 publications

References 9 publications

A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer

A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer

Successful Salvage Therapy of Irinotecan for Relapsed Hodgkin's Lymphoma.

DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

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