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
Abstract
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/m2 with a clearance of 11 L/h +/− 2.75 and a T1/2α 15 min and T½β 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.
Keywords: HOOI, 4-hydroperoxyifosfamide, brain tumors, non-tumor target therapy, no renal toxicity
1. Introduction
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 [3–5]. IFOS is still the phosphoramide mustard that is most used in sarcoma therapy; however, its use is hampered by requirement for hepatic activation and release of extracellular acrolein (ACR) and chloroacetaldehyde (CAA)—resulting in dose limiting cystitis, renal toxicity, and neurotoxicity, plus myelosuppression [6, 7].
4-Hydroperoxyifosfamide (HOOI, Figure 1) is a peroxide derivative of IFOS that spontaneously undergoes ring cleavage releasing acrolein and chloroacetaldehyde primarily in situ in cancer cells, not extracellularly in the general circulation as does IFOS [8–10]. The support data for HOOI’s anticancer activity and toxicity is reviewed here.
DEKK-TEC’s interest in HOOI was to document its potential usefulness as an anticancer agent and if it possesses any of IFOS’ toxicities – cystitis, renal tubular necrosis, and CNS alterations, all of which hamper the usefulness and utilization of IFOS [6, 7]. A secondary goal was to develop a stable form of HOOI for clinical use [11, 12]
Read full article at: http://www.intechopen.com/books/new-approaches-to-the-management-of-primary-and-secondary-cns-tumors/comparative-anticancer-activity-in-human-tumor-xenograft-models-preclinical-pharmacology-and-toxicol
Related article at: Pharmacology Help Online
Abstract
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/m2 with a clearance of 11 L/h +/− 2.75 and a T1/2α 15 min and T½β 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.
Keywords: HOOI, 4-hydroperoxyifosfamide, brain tumors, non-tumor target therapy, no renal toxicity
1. Introduction
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 [3–5]. IFOS is still the phosphoramide mustard that is most used in sarcoma therapy; however, its use is hampered by requirement for hepatic activation and release of extracellular acrolein (ACR) and chloroacetaldehyde (CAA)—resulting in dose limiting cystitis, renal toxicity, and neurotoxicity, plus myelosuppression [6, 7].
4-Hydroperoxyifosfamide (HOOI, Figure 1) is a peroxide derivative of IFOS that spontaneously undergoes ring cleavage releasing acrolein and chloroacetaldehyde primarily in situ in cancer cells, not extracellularly in the general circulation as does IFOS [8–10]. The support data for HOOI’s anticancer activity and toxicity is reviewed here.
DEKK-TEC’s interest in HOOI was to document its potential usefulness as an anticancer agent and if it possesses any of IFOS’ toxicities – cystitis, renal tubular necrosis, and CNS alterations, all of which hamper the usefulness and utilization of IFOS [6, 7]. A secondary goal was to develop a stable form of HOOI for clinical use [11, 12]
Read full article at: http://www.intechopen.com/books/new-approaches-to-the-management-of-primary-and-secondary-cns-tumors/comparative-anticancer-activity-in-human-tumor-xenograft-models-preclinical-pharmacology-and-toxicol
Related article at: Pharmacology Help Online
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