Comparative Preclinical Pharmacology and Toxicology for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOCPEN) — A Potential Neuro-Alkylating Agent for Glioblastoma (GBM) and Metastatic Cancers Involving the Central Nervous System

Morgan, Lee Roy; Rodgers, Andrew H.; Bastian, Gerard; EdmundBenes,; Waud, William S.; Papagiannis, Christopher; Krietlow, Branko S. Jursic Dan; Struck, Robert F.; LaHoste, Gerald J.; Thornton, Melody Luttrell Melissa; Stevens, Edward B.; Thompson, Rodger I.

doi:10.5772/58353

Cited by 4 publications

(26 citation statements)

References 14 publications

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“…DM-CHOC-PEN does not require hepatic activation and is active in nanogram quantities in vitro against melanoma GBM and breast cancer explants [7,8]. This is in contrast to DM-PEN (Figure 1) and other analogs that require hepatic activation [7].…”

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 88%

“…Hematology, renal, cardiac, pulmonary and neurological/cognitive profiles remained stable throughout the trials [8][9][10]. There have been no toxicities in the AYA aged group to date; however, no AYA subject treated has had preexisting liver or other chronic non-malignant illnesses.…”

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 99%

“…Unlike other penclomedines (e.g., PEN, NSC 338720, Figure 1), DM-CHOC-PEN is non-neurotoxic; however, it does cross the blood brain barrier (BBB) in animals and humans with responses reported in sarcoma, astrocytoma, melanoma, ALL, lung, and breast cancers involving the spinal and central nervous systems in clinical trials [10]. The drug accumulated (and was quantitated -61-120 ng/g of tumor tissue) in human sarcoma and lung cancer tissues involving the CNS/ SNS and was not found in adjacent normal brain/spinal tissue from subjects in Phase I/II trials [8][9][10].…”

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 99%

“…A total of fifty three (53) adult subjects with advanced cancers have been treated to date in clinical trials with DM-CHOC-PEN; forty-five subjects had CNS involvement (IND 68,876) [8,9]. The most common types of cancers treated have been metastatic lung, breast, melanoma, and primary brain (GBM, astrocytoma) cancers involving the CNS [10].…”

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 99%

“…Tumors in these age groups warrant effective innovative treatment. (Figure 1) is a polychlorinated pyridine cholesteryl carbonate designed and developed at DEKK-TEC that is lipophilic, electrically neutral and able to cross the blood brain barrier (BBB) [7][8][9]. The drug has been evaluated in Phase I/II clinical trials with objective responses and has improved over-all survival and PFS in subjects with advanced cancer involving the CNS and SNS (Table 1) (IND 68,876; NCT02889445) [9,10].…”

Section: Introductionmentioning

confidence: 99%

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The tolerance and safety of 4-Demethyl-4-cholesteryloxypenclomedine [DM-CHOC-PEN] in Adolescent and Young Adult (AYA) subjects with advanced malignancies

Rs¹,

Ware²,

Bhandari³

et al. 2017

J Transl Sci

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Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 88%

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 99%

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 99%

Section: -Demethyl-4-cholesteryloxypenclomedine [Dm-choc-pen]mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The tolerance and safety of 4-Demethyl-4-cholesteryloxypenclomedine [DM-CHOC-PEN] in Adolescent and Young Adult (AYA) subjects with advanced malignancies

Rs¹,

Ware²,

Bhandari³

et al. 2017

J Transl Sci

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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

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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.

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NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents

Rodgers¹,

Morgan²

2017

New Approaches to the Management of Primary and Secondary CNS Tumors

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Neurooncology anticancer drugs are no exception-their distribution and tissue interactions follow the general rules of classical pharmacology. In an attempt to assist with the new therapeutic approaches to manage cancers involving the central nervous system, classical chemobiodynamic compartment and pharmacokinetic models are discussed and illustrated. In addition, strategies and approaches for penetrating the blood brain barrier (BBB) are reviewed and modeled. Finally, in support of classical pharmacology, a new anticancer agent in clinical trial for brain tumors is reviewed as an example of clinical onco-neuropharmacology.

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Comparative Preclinical Pharmacology and Toxicology for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOCPEN) — A Potential Neuro-Alkylating Agent for Glioblastoma (GBM) and Metastatic Cancers Involving the Central Nervous System

Cited by 4 publications

References 14 publications

The tolerance and safety of 4-Demethyl-4-cholesteryloxypenclomedine [DM-CHOC-PEN] in Adolescent and Young Adult (AYA) subjects with advanced malignancies

The tolerance and safety of 4-Demethyl-4-cholesteryloxypenclomedine [DM-CHOC-PEN] in Adolescent and Young Adult (AYA) subjects with advanced malignancies

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

NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents

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