Myeloprotective Activity of Deoxyspergualin: Influence on Splenic Colony‐forming Cell Injury and Antitumor Activity of Mitomycin C in Mice

Nemoto, Kyuichi; Sugawara, Yumi; Ogino, Miwa; Mae, Takako; Abe, Fuminori; Takeuchi, Tomio

doi:10.1111/j.1349-7006.1992.tb01981.x

Japanese Journal of Cancer Research

1992

DOI: 10.1111/j.1349-7006.1992.tb01981.x

|View full text |Cite

Myeloprotective Activity of Deoxyspergualin: Influence on Splenic Colony‐forming Cell Injury and Antitumor Activity of Mitomycin C in Mice

Kyuichi Nemoto

Yumi Sugawara

Miwa Ogino

et al.

Abstract: We have examined the efficacy of deoxyspergualin (DSG) in protecting splenic colony‐forming cells (CFU‐S) from mitomycin C (MMC)‐induced damage. The main findings of the study are as follows. (1) When DSG was administered at doses of 1.5 and 3 mg/kg for 7 days before the MMC injection, the decrease of the femoral CFU‐S caused by MMC was diminished on the day after the MMC injection. The optimal dose was found to be 3 mg/kg. (2) In animals receiving 3 mg/kg DSG for at least 3 days preceding the MMC injection, t… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

1993

1994

Publication Types

Select...

Article5

Relationship

Self Cite0

Independent5

Authors

Journals

Cited by 5 publications

(1 citation statement)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DSG pretreatment had a minor suppressive effect on all immunotoxin-induced hematologic changes and ameliorated the elevated hematocrit induced by BR96 sFv-PE40 (Table 4). However, DSG caused a pronounced decrease in monocytes consistent with the general myelosuppression effect of DSG that had been previously reported (19).…”

supporting

confidence: 88%

Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity.

Siegall

Liggitt

Chace

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Immunotoxins are hybrid molecules composed of a cell-surface bin domain and a protein toxin moiety that together target sifc cell popaons for elimination. These Vascular leak syndrome (VLS) is the dose-limiting toxicity found in many clinical trials utilizing immunotoxins, including those prepared with blocked ricin, ricin A chain (in native and deglycosylated forms), and saporin (1-10). VLS is characterized in humans by hypoalbuminemia, weight gain, and edema, resulting from the extravasation offluids and proteins from the vascular system into the periphery. VLS restricts the use of immunotoxins in humans and in many cases necessitates either a significant reduction in dose or a complete cessation of therapy. While peripheral edema is clinically manageable, pulmonary edema can be life threatening. Recently, VLS was found to have contributed to the death of two B-cell lymphoma patients who were treated with anti-CD22-deglycosylated ricin A chain (9). Other toxic effects in patients treated with immunotoxins may be a result of VLS, including tachycardia, nausea, aphasias as a result ofcerebral edema, and myocardial damage (4).Other proteins also have been found to induce VLS in humans. Systemic administration of the cytokine interleukin 2 (IL-2) results in the development ofVLS when approaching doses that may provide antitumor efficacy in patients with metastatic cancer (11,12). VLS has also been observed in patients following treatment with granulocyte/macrophage colony-stimulating factor or the anti-GD3 antibody R24 (13,14).BR96 sFv-PE40 is a single-chain immunotoxin fusion protein that has been shown to cure established human tumor xenografts in both athymic rats and mice (15,16). In this study, a rat model for VLS was established following administration of BR96 sFv-PE40 at doses beyond those required for cures of tumor xenografts in rodent models. The identification of an animal model for VLS that closely approximates the human VLS response to immunotoxins provides an opportunity to evaluate specific drugs for their ability to block immunotoxin-induced VLS and to determine whether they affect the antitumor activity of BR96 sFv-PE40. MATERIALS AND METHODSReagents. The single-chain immunotoxin fusion protein BR96 sFv-PE40 was expressed in Escherichia coli and purified as described (16). Diphenhydramine hydrochloride was purchased from Elkins-Sinn (Cherry Hill, NJ). Cyclosporine A (CsA) was purchased from Sandoz Pharmaceutical. 15-Deoxyspergualin (DSG) was purchased from Nippon Kayaku (Tokyo). Dexamethasone (Dex) was purchased from Anpro Pharmaceuticals (Arcadia, CA).Toxicity Studies. Six-to 8-week-old female Wistar Furth and Rowett, nu/nu (athymic) rats (Harlan-Sprague-Dawley) were i.v. injected with various amounts of BR96 sFv-PE40 (0.25-4 mg/kg). After 24 hr, they were euthanized by exposure to C02, and the tissues were analyzed using gross and microscopic techniques. Cardiac blood was collected from comatose animals and placed either in serum collection tubes for blood chemistry analysis or in EDT...

show abstract

supporting

confidence: 88%

Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity.

Siegall

Liggitt

Chace

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

Phase II study of deoxyspergualin in metastatic breast cancer

et al. 1994

View full text Add to dashboard Cite

We conducted a phase II trial of the novel immunomodulatory/cytotoxic agent 15-deoxyspergualin in patients with metastatic breast cancer who had failed treatment with front-line chemotherapy. Thirty-eight courses of treatment were administered to fourteen patients enrolled in this trial, 25 at a dose of 1800 mg/m2/d (dose level 0) and 13 at a dose of 2150 mg/m2/d (dose level +1) administered by continuous intravenous infusion for 5 days. Treatment was well tolerated with neuromuscular side-effects (myalgias, paresthesias) and granulocytopenia (nadir granulocyte count of 0.50-0.99 x 10(9)/l) in two and three courses, respectively, as the only grade III toxicities. The neuromuscular toxicity of deoxyspergualin is probably related to the occurrence of hypomagnesemia. No partial or complete responses were observed in this study. One patient achieved a minor response but had progressive disease 65 weeks after enrollment. The response was observed coincident with an increase in T4/T8 ratio in the peripheral blood. The median time to progression for the entire cohort was eight weeks (range, 4-65 weeks). There was no clinical evidence of immunosuppression and no decrease in total peripheral blood lymphocyte counts or helper T-cells was observed. At the doses and schedule employed in this trial, deoxyspergualin does not appear to have significant activity against metastatic breast cancer resistant to front-line chemotherapy. The correlation between hypomagnesemia and neuromuscular toxicity of deoxyspergualin is an intriguing, previously unknown observation and requires further investigation.

show abstract

Improvement of mitomycin C‐ and cyclophosphamide‐induced thrombocytopenia and leucocytopenia by prior treatment with deoxyspergualin in dogs

et al. 1994

View full text Add to dashboard Cite

Deoxyspergualin (DGS) is a new immunosuppressant which has shown inhibitory haemopoietic activity. We investigated the myeloprotective effect of DSG against the haemopoietic injury of mitomycin C (MMC) or cyclophosphamide (CYC) by measuring peripheral blood cell numbers in dogs. DSG given at 5 mg/kg on days 3, 2 and 1 before, or at 10 mg/kg on either days 2 and 1 before or on day 1 before and the day of injection of MMC at 0.25 mg/kg ameliorated both the thrombocytopenia and leucopenia caused by MMC. This ameliorative effect was more evident on platelet counts than on white blood cell counts. In addition, the leucopenia and thrombocytopenia induced by a single injection of CYC at 10 mg/kg was also ameliorated by prior DSG administration. These findings suggest that DSG may be useful in protecting against the haemopoietic damage induced by chemotherapeutic agents in the treatment of cancer.

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

customersupport@researchsolutions.com

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Myeloprotective Activity of Deoxyspergualin: Influence on Splenic Colony‐forming Cell Injury and Antitumor Activity of Mitomycin C in Mice

Cited by 5 publications

References 11 publications

Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity.

Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity.

Phase II study of deoxyspergualin in metastatic breast cancer

Improvement of mitomycin C‐ and cyclophosphamide‐induced thrombocytopenia and leucocytopenia by prior treatment with deoxyspergualin in dogs

Contact Info

Product

Resources

About