Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide

Struck, Robert F.; Dykes, Donald J.; Corbett, Thomas H.; Suling, William J.; Trader, M W

doi:10.1038/bjc.1983.2

Cited by 37 publications

(13 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The rationale for the preclinical development of HOOI was based on observed antitumor activity vs. intracranially implanted human tumor xenografts growing in mice and an anticipated reduction in renal toxicity and encephaloneuropathy that occur with standard IFOS and IPM therapy (1,8,9).…”

Section: Discussionmentioning

confidence: 99%

“…Isophosphoramide mustard (IPM) (Figure 1) is the active metabolite of ifosfamide (IFOS) and a bifunctional DNA alkylator that generates guanine-cytosine interstrand cross-linking in G-X-C sequences producing cell death [1,2]. Although IPM is the ultimate alkylator that is derived from IFOS, it has been removed from clinical trials because of lack of sufficient anticancer activity in clinical trials [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comparative Anticancer Activity in Human Tumor Xenograft Models, Preclinical Pharmacology and Toxicology for 4- Hydroperoxyifosfamide (HOOI): A Potential Neuro-Alkylating Agent for Primary and Metastatic Cancers Involving the Central Nervous System

Morgan¹,

Rodgers²,

Bastian³

et al. 2017

New Approaches to the Management of Primary and Secondary CNS Tumors

View full text Add to dashboard Cite

Background: 4-Hydropeoxyifosfamide (HOOI) is a hydroperoxy derivative of ifosfamide that was developed as an anticancer agent that can penetrate the blood-brain barrier (BBB), which can be potentially useful in the management of brain tumors. Methods:A novel synthetic scheme for HOOI is presented and verified. HOOI and an HOOI L-lysine salt were prepared and mice implanted intracranially (IC) and in the mammary fat pad with human U251 glioblastoma, D54 glioblastoma, and MX-1 breast tumor xenografts and treated with HOOI IP once daily for 1-5 days. The animals were monitored for responses, increased long-term survival (ILS) and long-term survival (LTS). Mice, rats, and dogs received single IV doses of HOOI in a wide range of concentrations and results are compared and presented herein.Results: HOOI has been synthesized as per a new route in 67% yield. The drug is stable when frozen in the absence of moisture; however, as a lysine salt the drug is stable in solution and as a lyophilized product. HOOI produced complete responses with improved long-term survival against IC implanted U251 glioblastoma, D54 glioblastoma, and MX-1 breast tumor xenografts in mice. The drug was superior to 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHC-PEN) and BCNU vs. IC implanted tumor models. The HOOI lysine salt demonstrated equal activity to that of HOOI alone. Over all, the drug was well tolerated. Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 39 mg/m 2 with a clearance of 11 L/h +/− 2.75 and a T 1/2α 15 min and T ½β 5.30 h for a 70 kg human patient. The presented toxicity data plus strong antineuro-oncology activity supports DM-CHOC-PEN's proposed use as a treatment for CNS malignancies. The drug is being prepared for Phase I trial studies in the US-IND pending.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative Anticancer Activity in Human Tumor Xenograft Models, Preclinical Pharmacology and Toxicology for 4- Hydroperoxyifosfamide (HOOI): A Potential Neuro-Alkylating Agent for Primary and Metastatic Cancers Involving the Central Nervous System

Morgan¹,

Rodgers²,

Bastian³

et al. 2017

New Approaches to the Management of Primary and Secondary CNS Tumors

View full text Add to dashboard Cite

show abstract

“…[2] 3-high energy atom chains, thus the drug more than fits the criteria proposed earlier in this chapter (3). In addition, HOOI does not require activation by the liver and spontaneously undergoes conversion to IPM and cross-links with nuclear DNA via major groove alkylation -N 7 -guanine, forming G-X-C adducts [39].…”

Section: High Energy Drugmentioning

confidence: 99%

“…IFOS is a well-known anticancer agent that requires hepatic activation to 4-HO-IFOS which spontaneously undergoes hydrolysis with ring opening resulting in isophosphoramide mustard (IPM) [ Fig. 14], the latter is the active cytotoxic form of IFOS [37][38][39]. As part of the IFOS activation process, hepatic metabolic dechloroethylation releases chloroacetaldehyde, which has been proposed to be the major cause of IFOS associated neurotoxicity [40].…”

Section: High Energy Drugmentioning

confidence: 99%

A Rational for Novel Anti-NeuroOncology Drugs

Morgan¹

2013

Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications

View full text Add to dashboard Cite

“…7 These active compounds have a very short half-life of a few minutes 8,9 in plasma. Ifosfamide demonstrates antineoplastic activity against experimentally induced colon cancer [10][11][12] and it was suggested that it may be useful in the treatment of peritoneal cancer in humans as well. 13 In the case of peritoneal carcinomatosis the administration of ifosfamide-converting enzyme into the abdominal cavity provides activation of ifosfamide directly at the site of tumor development, thus circumventing activation of the prodrug in the liver.…”

Section: Introductionmentioning

confidence: 99%

Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide

et al. 2005

View full text Add to dashboard Cite

The prognosis of peritoneal spread from gastrointestinal cancer and subsequent malignant ascites is poor, and current medical treatments available are mostly ineffective. Targeted chemotherapy with intraperitoneal prodrug activation may be a beneficial new approach. L293 cells were genetically modified to express the cytochrome P450 enzyme 2B1 under the control of a cytomegalovirus immediate early promoter. This CYP2B1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcellt). Adult Balb/c mice were inoculated intraperitoneally with 1 Â 10 6 colon 26 cancer cells, previously transfected with GFP to emit a stable green fluorescence, by injection into the left lower abdominal quadrant. Two or five day's later animals were randomly subjected to either i.p. treatment with ifosfamide alone or ifosfamide combined with microencapsulated CYP2B1-expressing cells. Peritoneal tumor volume and tumor viability were assessed 10 days after tumor inoculation by means of fluorescence microscopy, spectroscopy and histology. Early i.p. treatment with ifosfamide and CYP2B1 cells resulted in a complete response. Treatment starting on day 5 and single-drug treatment with ifosfamide resulted in a partial response. These results suggest that targeted i.p. chemotherapy using a combination of a prodrug and its converting enzyme may be a successful treatment strategy for peritoneal spread from colorectal cancer.

show abstract

Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide

Cited by 37 publications

References 16 publications

Comparative Anticancer Activity in Human Tumor Xenograft Models, Preclinical Pharmacology and Toxicology for 4- Hydroperoxyifosfamide (HOOI): A Potential Neuro-Alkylating Agent for Primary and Metastatic Cancers Involving the Central Nervous System

Comparative Anticancer Activity in Human Tumor Xenograft Models, Preclinical Pharmacology and Toxicology for 4- Hydroperoxyifosfamide (HOOI): A Potential Neuro-Alkylating Agent for Primary and Metastatic Cancers Involving the Central Nervous System

A Rational for Novel Anti-NeuroOncology Drugs

Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide

Contact Info

Product

Resources

About