Preclinical Activity of 4-Demethyl-4-cholesteryloxycarbonylpenclomedine in Melanoma.

BACKGROUND/AIM: Temozolomide plays a role in treating melanoma refractory to immunomodulatory and mitogen-activated protein kinase-targeted approaches, but its efficacy is limited. 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate. Its mechanism of action is considered to be via alkylation/adduct formation with N7-guanine. It demonstrated activity in intracranial implanted human glioma and breast cancer xenograft mouse models. The activity of DM-CHOC-PEN in melanoma models was assessed. MATERIAL AND METHODS: B-16 melanoma cells were exposed to DM-CHOC-PEN at different concentrations to assess proliferation and survival. B-16 cells were implanted subcutaneously into the flank of adult female C57BL mice which were then were treated with 200 mg/kg DM-CHOC-PEN intraperitoneally daily for 5 days in the setting of palpable subcutaneous tumor. Survival was compared to mice treated with temozolomide or saline. Five mice were treated per group. RESULTS: In vitro, the respective half-maximal inhibitory concentrations of DM-CHOC-PEN and temozolomide were 0.5 and ≥3.0 µg/ml. Floating, heavily melanotic cells formed and these cells were separated, analyzed, and contained 10-90 ng DM-CHOC-PEN per 105 cells. The improvement in survival of mice treated with DM-CHOC-PEN or temozolomide relative to saline controls was 142% and 78%, respectively. CONCLUSION: Longer survival was seen with DM-CHOC-PEN in a C57BL murine model relative to temozolomide and saline-treated controls, supporting the development of clinical trials assessing the efficacy of DM-CHOC-PEN as treatment for metastatic melanoma.

Treatment of recurrent metastatic uterine leiomyosarcoma of the spine: a multimodality approach using resection, radiosurgery, and chemotherapy.

The authors describe the case of a patient who initially presented with uterine leiomyosarcoma (LMS) that later metastasized to the spine. The patient was treated at another institution for her primary uterine LMS, undergoing resection followed by adjuvant chemotherapy. After several years of disease remission, the patient presented in January 2011 to the authors' institution with recurrent uterine LMS metastatic to the spine, which has been treated with multiple therapeutic modalities in a combination of surgery, radiosurgery, and chemotherapy. As a result of this approach, the patient has been progression free for 35 months since her presentation (April 2011 to March 2014). We herein describe our experience treating this patient with recurrent uterine LMS of the spine and suggest that patients with recurrent uterine LMSs should be considered for treatment using a multimodality approach with emphasis on enrollment into clinical trials.

BACPTDP: a water-soluble camptothecin pro-drug with enhanced activity in hypoxic/acidic tumors.

UNLABELLED: Hypoxia is a common feature of solid tumors. Up-regulation of hypoxia-inducing factor-1 (HIF-1) occurs in the majority of primary malignant tumors and in two-thirds of metastases, while most normal tissues are negative. HIF-1 induces the glycolytic phenotype, which creates an acidic extracellular microenvironment and associated pH gradient such that drugs that are weak acids are selectively taken up and retained in acidic tumors. 7-Butyl-10-amino-camptothecin (BACPT) is a prime example of an agent that can exploit the tumor pH gradient for enhanced selectivity. PURPOSE: This study profiles the antitumor activity of BACPT in vitro and its water-soluble dipeptide ester, BACPTDP, in vivo. METHODS: Antitumor activity was evaluated by proliferation assays in cancer cell lines and in murine xenograft models for human neuroblastoma (IMR-32), colon (HT29), ovarian (SK-OV-3), pancreatic (Panc-1), glioma (SF-295) and non-small-cell lung (NCI-H460) cancers. RESULTS: BACPT had superior antiproliferative activity compared to established drugs in monolayer cultures of human neuroblastoma and pancreatic tumor cell lines and in 3-dimensional histocultures of colon and primary ovarian cancer. Antitumor activity of BACPTDP was comparable to irinotecan in IMR-32, HT29, SF-295 and NCI-H460 xenografts, significantly greater in SK-OV-3 and in Panc-1 where complete regressions were observed. Combination of BACPT with gemcitabine produced additive to synergistic interactions in Panc-1 cells that were independent of drug ratio and optimal when gemcitabine was administered 24 h prior to BACPT. CONCLUSIONS: BACPTDP is a water-soluble camptothecin pro-drug that spontaneously generates the lipid-soluble active agent, BACPT. This topoisomerase inhibitor exploits solid tumor physiology for improved selectivity and activity against multiple tumor types with particular promise for use in treating pediatric neuroblastoma and pancreatic carcinoma.

Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents.

PURPOSE: The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors. METHODS: Derivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC). RESULTS: Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts. CONCLUSION: The activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.

4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007): a topical treatment for cutaneous metastases from malignant cancers.

PURPOSE: This study is to document the activity and acceptability for a new topical agent, A-007, in the treatment of cutaneous metastases from cancer. PATIENTS AND METHODS: This is a multicenter study involving 27 patients with inoperable skin lesions from histologically confirmed cancers of the breast and oral cavity, non-Hodgkin's lymphoma, Kaposi's sarcoma, and angiosarcoma that had failed radiotherapy or systemic treatment. A-007, as a 0.25% gel, was applied twice daily to the areas of cancer to be measured as well as applied to a healthy control area distant from the cancer areas. An untreated cancer area was also included and documented as a cancer control. RESULTS: The overall objected response rate with A-007 was 26%, with an additional 19% minimum response/stabilization of cancer. For patients with breast cancer, hormonal status did not have an impact on response. The median duration of response was 15 weeks (with one patient having a response for 3.5 years). Toxicities observed were itching, burning, and a rash, in 6 of the 27 patients. The skin toxicities were in the cancer-treated fields; none were observed in the A-007 control areas. All irritated areas cleared while continuing treatment, and the tumor lesions in the areas of itching also improved. CONCLUSION: A-007, as a 0.25% gel, is confirmed as an effective palliative treatment option for cutaneous metastases from cancers. Skin reactions were minimal, tolerated, and no cessation of treatment was required.

Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide.

BACKGROUND: Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols. METHODS: Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared. RESULTS: For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T(1/2alpha) 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T(1/2) was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation. CONCLUSIONS: Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m(2) with a clearance of 39.5 l/h, and a T(1/2) of 1 h 45 min for a 70-kg patient.

Design, synthesis, and anticancer properties of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and analogues.

4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a phase I clinical trial in advanced cancer with minimal toxicity, and impressive objective responses were noted. A-007 possesses three moieties that appear to have an influence on its anticancer activities: diphenylmethane, hydrazone, and dinitrophenyl. The goals of this study were to modify A-007's chemical moieties with the ultimate goal of maximizing its anticancer activity through increased planarity and introduction of functional groups. Thirty-five phenylhydrazone analogues of A-007 were synthesized and evaluated in vitro in a human primary cancer explant assay. Anticancer activities for selected analogues were also assayed for activity vs established human/murine cell lines. One-hundred-eighty-six fresh human solid tumors were used to screen for anticancer activity. Selected analogues were assayed for therapeutic indices (vs GM-CFC from bone marrow) in preparation for preclinical studies. Several polyaryl phenylhydrazones demonstrated improved cytotoxic activities by factors of 10(2)-10(3) when compared with A-007. However, the polyaryl quinone moieties of the latter analogues introduced potential toxic properties (cardiac, hematological) that do not exist with A-007.

Anticancer activity for 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) analogues and their abilities to interact with lymphoendothelial cell surface markers.

The structure of the anticancer agent 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has been modified through SAR and by incorporating barbituric acid, pyridine, quinoline, and alkylcarboxylic acids into A-007's moieties. Analogue anticancer activity and interacting with CD surface markers on a T-cell leukemia cell line were evaluated and the correlation between SAR and biological properties are discussed.