Phase II clinical trial of 4′-O-Tetrahydropyranyl-Adriamycin (THP-Adriamycin) in recurrent squamous cell carcinoma of the head and neck

Summary Fourteen patients previously treated with surgery, radiotherapy, and/or chemotherapy for primary squamous cell carcinoma of the head and neck were treated with 4-O-tetrahydropyranyl-Adriamycin (THP-adriamycin) for locally or distantly recurrent disease. The starting dose was 60 mg/m² by i.v. infusion, with courses repeated every 3 to 4 weeks. A total of 34 courses of treatment were delivered (median, 2; range, 1–6). All patients were evaluable for response and toxicity. There were no responses. Severe (grade 3 or 4) neutropenia occurred in 11 patients. Thrombocytopenia, anemia, and gastrointestinal toxicity were modest, and no hepatic, renal, or cardiac toxicity was observed. The lack of response in association with severe neutropenia and moderate other toxicities using this dose and schedule of THP-Adriamycin should be taken into consideration prior to the pursuit of further study of this compound in a similar patient population.     

Phase II trial of 13-cis-retinoic acid plus interferon-α in recurrent head and neck cancer

13-cis-retinoic acid (isotretinoin) and interferon- have limited activity as single agents in advanced cancer. Preclinical data indicate that these agents have different mechanisms of action and, in combination have greater activity (that is, the ability to modulate growth and differentiation) in a number of malignant cell types than either agent alone. In clinical trials, the new biological regimen of 13-cis-retinoic acid and interferon- was shown to have major activity in advanced squamous cell carcinoma of the skin and cervix. We conducted a phase II trial of this regimen in recurrent squamous cell carcinoma of the head and neck. Of the 21 evaluable patients, none had a complete response, and only one had a partial response (5%). Two patients had minor responses, four had stable disease, and 14 experienced disease progression. Five patients developed grade 3 toxic effects, including skin toxicity, fatigue, headache, and anorexia/weight loss. The median survival duration was 25.5 weeks (range, 4–95). The combination of 13-cis- retinoic acid and interferon- at this dose and schedule is ineffective for the treatment of recurrent squamous cell carcinoma of the head and neck.     

Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer

Summary This phase II trial was initiated to assess the efficacy and safety of oral vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Eligible patients must have recurrent and/or metastatic head and neck cancer unresponsive to or intolerant of conventional chemotherapy. Patients must have measurable disease, adequate hematologic, hepatic, and renal function, and be able to swallow capsules. Four or more weeks must have elapsed since prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy, and patients must have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Thirteen patients were enrolled (9 males); 1 withdrew consent prior to starting therapy. Twelve patients received oral vorinostat 400 mg once daily and were evaluable for response. The median age was 54 years (range 40–82). All patients had received prior chemotherapy (including 10 with platinum- or taxane-based combination therapy), and 9 had prior radiation therapy. No confirmed partial or complete responses were observed. One unconfirmed partial response was seen. Three patients had stable disease ranging from 9 to 26 weeks. Nine patients discontinued due to progressive disease, two withdrew consent, and one discontinued therapy for grade 3 anorexia. Grades 3–4 drug-related toxicities included thrombocytopenia (n = 3), anorexia (n = 2), and dehydration (n = 2). Oral vorinostat 400 mg qd was generally well tolerated but did not demonstrate efficacy as defined by tumor response in this small group of heavily pre-treated patients. Presented in part as a poster at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5–8, 2004. This research has not been published elsewhere and has not been submitted simultaneously for publication elsewhere.     

Phase I trial and pharmacokinetic study of intravenous and oral α-Difluoromethylornithine

Eflornithine-HCl (-difluoromethylornithine or DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity in cell culture and animal tumor models. This phase I study was designed to determine and compare toxicity and the maximally tolerated dose of a 4-day course of DFMO given to patients in oral, continuous intravenous infusion or pulse intravenous infusion forms. Twenty-four patients were entered into this study: 8 received intravenous pulse drug, 10 intravenous continuous infusion of drug, and 6 oral DFMO. The most frequent toxicity was nausea and vomiting which occurred in 9 courses of oral drug. Only two patients receiving intravenous DFMO had nausea and vomiting. Clinically significant thrombocytopenia and audiometric abnormalities were not encountered in contrast to previous experience with 28-day courses of oral DFMO. The maximally tolerated dose of a four-day course of oral DFMO was 3.75 gm/M² every 6 hours. The maximally tolerated dose of intravenous pulse and continuous infusion DFMO was not attained. Pharmacokinetic studies demonstrated that the intravenous schedules achieved higher plasma levels of DFMO than those previously obtained with chronic oral dosing.Presented in part at the 20th Annual Meeting of the American Society of Clinical Oncology, May 1984, Toronto, Ontario, Canada     

Phase I study of escalating dose mitoxantrone in combination with α-2-interferon in patients with advanced solid tumors

In vitro and preclinical in vivo data have shown a synergistic antitumor activity between -interferon and some antiproliferative agents. A phase I study of the concurrent administration of interferon- 2 and mito-xantrone was initiated, to determine the maximum tolerated dose of mitoxantrone given i.v. every 3 weeks in escalating doses combined with a fixed dose of s.c. interferon 2 (6 × 10⁶ IU three times per week³), in patients with advanced solid tumors resistant to conventional chemotherapy. At least three evaluable patients were entered in each dose level of mitoxantrone starting at 4 mg/m², with no escalations allowed in the same patient. Twenty-seven patients received a total of 101 cycles and five dose-levels were explored (4-6-8-10-12 mg/m² of mitoxantrone). The dose-limiting toxicities were leukopenia and granulocytopenia at 12 mg/m² of mitoxantrone, at which dose hematological toxicity occurred in > 50% of cases, with one patient presenting grade 4 leuko-granulocytopenia. No severe thrombocytopenia occurred. In the majority of patients transient hepatic enzyme elevations and a flu-like syndrome due to interferon a 2 were observed in all dose-levels explored. These observations suggest that the hepatotoxic effects of interferon a 2 do not emphasize mitoxantrone side-effects if given simultaneously. When mitoxantrone is administered with 6 × 10⁶ IU of interferon 2, the recommended dose for future phase II studies is 10 mg/m²/weeks³ with escalation up to 12 mg/m² in selected patients if such a combination is well tolerated in terms of myelosuppression. Regarding therapeutic activity, four out of 25 (16%) cases evaluable for response achieved a partial response. In conclusion the concomitant administration of recombinant interferon 2 and mitoxantrone allows the possibility to give a therapeutic dosage of both agents. Because the combination of the two agents was fairly well tolerated and antitumor activity was observed, phase II trials are warranted.     

Phase II study of 2′-deoxycoformycin in patients with renal cell carcinoma

Summary The National Cancer Institute of Canada Clinical Trials Group undertook a phase II study of 2-deoxycoformycin in patients with metastatic renal cell carcinoma. When 2-deoxycoformycin 4 mg/m² was administered intravenously weekly for three weeks then every two weeks no significant antitumor activity was noted in 19 evaluable patients. Toxic effects experienced were as expected, consisting primarily of nausea/vomiting, anorexia, and lethargy. It is concluded that 2-deoxycoformycin at this dose and schedule has no clinical activity in the treatment of metastatic renal cell carcinoma.     

Phase I and phase II clinical trials for the treatment of male sexual dysfunction—a systematic review of the literature

Introduction: The prevalence of sexual dysfunctions has increased over the last decades; despite a number of available treatments for erectile dysfunction (ED), premature ejaculation (PE), and Peyronie’s disease (PD), still several unmet therapeutic needs deserve to be fulfilled. The aim of this review is to detail on phase I and II clinical trials investigating novel medical treatments for ED, PE, and PD.

Areas covered: We conducted a systematic review of the literature including both published and ongoing phase I and II registered trials focused on medical treatment of ED, PE, and PD during the last 5 years. A total of 35 trials have been identified. Most studies (63%) investigated ED treatments and 26% were still ongoing. Stem cells (SCs) therapy was assessed in 28% of trials.

Expert opinion: SCs therapy represent a promising treatment for ED although only few patients have been treated to date. Likewise, the oral selective oxytocin receptor antagonists for treating PE showed excellent safety profile and deserve further investigations in phase III trials. Preliminary results of novel topical treatments for PD with fibrinolytic and antiinflammatory drugs are encouraging, but urgently need to be confirmed in large placebo-controlled trials.     

Phase II study of esorubicin (4′-deozydoxorubicin) in advanced epithelial carcinoma of the ovary: A Gynecologic Oncology Group study

Summary Twenty-six patients with advanced, measurable epithelial carcinoma of the ovary were treated with 76 courses of esorubicin at doses ranging from 20–30 mg/m² every 3 weeks. All patients are evaluable for toxicity and response. All patients had received prior therapy including radiation therapy in 9, non-anthracycline chemotherapy in 25, and surgery in 25. All patients were GOG performance status 0, 1 or 2. Two partial responses were seen. Severe (grade 3 or 4) leukopenia, thrombocytopenia, and anemia were seen in 13, 1 and 4 patients, respectively. Moderate gastrointestinal toxicity was also noted. Alopecia and mucositis were rare. Phlebitis was not seen. Neither clinical congestive cardiomyopathy nor decrement in left ventricular ejection fraction was observed. We conclude that using this dose and schedule of esorubicin as second-line chemotherapy in ovarian epithelial neoplasms lacks significant activity and is associated with moderate toxicity.     

Phase I trial of high-dose infusional hydroxyurea,high-dose infusional 5-fluorouracil and recombinant interferon-α-2a in patients with advanced malignancies

The ribonucleotide reductase inhibitor, hydroxyurea (HU), augments the cytotoxic effects of 5-fluorouracil (5FU)in vitro; both drugs are synergistic with interferon- (IFN)in vitro. The aim of this phase I study was to determine the maximal duration of HU, 4.3 g/m², administered as a parenteral infusion in combination with 5FU, 2.6 g/m² administered over 24 hrs each week, + IFN, 9 MU, subcutaneously three times per week. There were 26 patients enrolled and evaluable. This included 14 patients with colorectal cancer of whom 13 had been previously treated, and 12 patients with other refractory malignancies (pancreas, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and others), of whom 10 were previously untreated. The dose-limiting toxicity of this regimen was myelosuppression. This prohibited dose escalation of HU above the starting dose (24 hrs) on a 6-weeks-on, 2-weeks-off therapy schedule. When filgrastim, 480 g, was administered subcutaneously on days 3–6, the duration of HU could be extended to 48 hrs on a 2-weeks-on, 1 -week-off therapy schedule. There were two instances of fatal infection, one in a patient with a rectovaginal fistula with neutropenic sepsis and the second in a patient with non-neutropenicClostridium septicum sepsis. All therapy was administered in the ambulatory setting. There were three responders, all among previously untreated patients. High-dose parenteral hydroxyurea, 4.3 g/m² administered over 24 hrs, can be safely combined with high-dose weekly 5FU, 2.6 g/m² over 24 hrs + IFN, 9 MU subcutaneously three times per week, without filgrastim in the ambulatory setting. Parenteral hydroxyurea, 4.3 g/m² over 24 hrs daily × 2 can also be combined with high-dose 5FU + IFN, but requires the addition of filgrastim to avoid severe myelosuppression.     

Phase II study of esorubicin (4′-deoxydoxorubicin) in advanced or metastatic squamous carcinoma of the uterine cervix: A Gynecologic Oncology Group study

Summary Twenty-eight patients with advanced, measurable squamous carcinoma of the uterine cervix were treated with 62 courses of esorubicin at doses ranging from 20–35 mg/m² every three weeks. All patients were evaluable for response and toxicity. All patients had received prior therapy including radiation therapy in 28, chemotherapy in 23, and surgery in 11. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1 or 2. There were no responses seen. Severe (grade 3 or 4) leukopenia, thrombocytopenia, and anemia were seen in 13, 3, and 9 patients, respectively. Gastrointestinal toxicity as well as alopecia were the other adverse effects. Mucositis and phlebitis were not seen. Neither clinical congestive cardiomyopathy nor decrement in left ventricular ejection fraction was observed. Lack of response in association with moderate toxicity using this dose and schedule of esorubicin in squamous carcinoma of the cervix previously treated with chemotherapy makes further study as a salvage agent unwarranted. Address for offprints: GOG Headquarters, Suite 1945, 1234 Market Street, Philadelphia, PA 19107, USA.     

Phase II study of docetaxel alternating with cisplatin in chemotherapy-naïve patients with advanced non-small cell lung cancer

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.     

Phase II trial of 4′ deoxydoxorubicin (DXDX) for unresectable non-small cell bronchogenic carcinoma

Summary A phase II trial of 4 Deoxydoxorubicin (DXDX) was conducted in unresectable previously untreated non-small cell lung cancer patients. DXDX was administered every 3 weeks by short intravenous infusion at a starting dose of 30 mg/m², with dose escalation to 40 mg/m² toxicity permitting. Four responses, all partial, were observed in 35 evaluable patients, for a response rate of 11% (95% confidence limits 3.2% and 26.7%). Myelosuppression was the dose-limiting toxicity. Cardiotoxicity was not seen. DXDX has minimal activity against non-small cell lung cancer as a single agent at the dosage used in this study.Supported in part by Public Health Service Grant CA-21742 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services     

Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: from bench to bedside?

Head and neck squamous cell carcinoma (HNSCC) is a group of tumors known to be sensitive to chemotherapy and radiotherapy in patients who are treatment naive. However, when recurrences do occur, these tumors generally become resistant and objective responses to therapy at that point tend to be less effective. There has been an increasing interest in developing novel molecular-targeted agents that specifically modulate growth factor and signaling pathways that are unregulated in HNSCC tumor cells. Combinations of vascular endothelial growth factor and mammalian target of rapamycin inhibitors have been used in some types of neoplasms, but no such efforts have been made in HNSCC. In this study, we investigated the in vitro, in vivo, and clinical effects of the temsirolimus (mammalian target of rapamycin inhibitor, Tem) and bevacizumab (antivascular endothelial growth factor antibody, Bev) combination. In-vitro studies were carried out on the A431 human squamous epidermoid carcinoma cell line and in-vivo studies were carried out on A431 tumor cells implanted on female Nu/Nu*nuBR (athymic nude) mice. Also, the effectiveness of the Tem and Bev combination was tested clinically in two separate clinical cases of chemoresistant HNSCC. The in-vitro, in-vivo, and clinical results showed that this combination can be significantly effective. In conclusion, we discuss the theoretical basis of the molecular pharmacological interactions between Bev and Tem that could explain these good results. If the therapeutic index is ultimately well determined, the antitumor effect of Bev and Tem is very likely to yield fruitful results.     

Further study of prerequisites for the enhancement by α-adrenoceptor antagonists of the release of noradrenaline

Summary Segments of the rabbit ear artery were preincubated with (–)-³H-noradrenaline and then perfused/superfused and stimulated by transmural electrical pulses. The outflow of ³H-noradrenaline and total tritium was determined.In the first series of experiments, stimulation periods of approximately constant length (50 s) were used (cocaine 5 M present). Thirteen pulses (0.25 Hz) elicited an overflow of ³H-noradrenaline of 0.024% of tissue tritium; 26 pulses (0.5 Hz) elicited an overflow of 0.059%, and 52 pulses (1 Hz) of 0.166%. Rauwolscine 1 M did not change the overflow evoked by 13 pulses, increased that evoked by 26 pulses and increased most markedly that evoked by 52 pulses. Phentolamine 1 M decreased the overflow at 13, did not change the overflow at 26, and increased the overflow at 52 pulses. Corynanthine 1 M decreased the overflow at 13, and did not change the overflow at 26 and 52 pulses. The effect of tetraethylammonium (TEA) 100 M was opposite to that of rauwolscine; it increased most markedly the overflow evoked by 13 pulses, increased less that evoked by 26 pulses, and least the overflow at 52 pulses.In the second series of experiments, the frequency of stimulation was kept constant (2 Hz). In the absence of cocaine, 10 pulses elicited an overflow of ³H-noradrenaline of 0.023% of tissue tritium; 20 pulses elicited an overflow of 0.043%, and 40 pulses of 0.089%. Phentolamine 1 M did not change the overflow evoked by 10 pulses, increased that evoked by 20 pulses, and increased most markedly that evoked by 40 pulses. TEA 100 M increased the evoked overflow at all pulse numbers. Similar results were obtained in the presence of cocaine 5 M.The results demonstrate that the enhancement by -adrenoceptor antagonists of the release of noradrenaline depends on the biophase concentration of noradrenaline. Under the present conditions, graded increases in biophase noradrenaline concentration led to graded increases in the effect of the antagonists. A second prerequisite for the release-enhancing effect appears to be a sufficient length of the pulse train. Under the present conditions, graded increases in train length up to about 20s led to graded increases in the effect of the antagonists, even though the average biophase concentration of noradrenaline did not change with the pulse train length. This pattern of effects of the -antagonists is not shared by at least one other release-enhancing drug, namely TEA.     

Optimal modeling for phase I design of a two drug combination—results of a phase I study of cisplatin with 9-nitrocamptothecin

Combination of platinum with topoisomerase-I inhibitors are synergistic. The objectives of this study were to determine MTD range and toxicity profile of combinations of oral 9-nitrocamptothecin (9NC) and intravenous cisplatin in patients with refractory solid tumors. Each course was 28 days starting on day 1 with cisplatin, and then 9NC daily for 5 days/week for three weeks. A new two arm crossing design was created: patients in arm 1 were treated with at the single agent recommended dose of cisplatin (50 mg/m(2)), and increasing doses of 9NC and in arm 2 with the single agent recommended dose of 9NC (1.5 mg/day) and increasing dose of cisplatin. Once a dose limiting toxicity was observed, the dose of the escalated drug was decreased by one level, and the fixed-dose drug was then escalated. A 3 + 3 design was used. Eligibility criteria were standard for a phase I trial. Pharmacokinetics was performed. Eighteen patients were treated on Arm 1, 3 at the crossing level, and 33 on Arm 2. Dose limiting toxicities were gastrointestinal at the crossing dose level. After crossing, prolonged grade 3 thrombocytopenia was the DLT in arm 1, and grade 4 neutropenia in Arm 2. Only one patient with ovarian cancer had a partial remission, and 12 patients had disease stabilization (24% of clinical benefit). A Bayesian optimal dose finding was tested post-facto. The recommended doses for phase II studies by the 3 + 3 design are cisplatin 60 mg/m(2) and 9NC 1.25 mg/day and cisplatin 40 mg/m(2) and 9NC 2.0 mg/day. The Bayesian optimal dose finding suggested a different solution, closest to that of the latter dosing which may be less toxic.     

Combinatorial synthesis and evaluation of α-iminocarboxamide-nickel(II) catalysts for the copolymerization of ethylene and a polar monomer

Late-transition metal catalysts used for olefin polymerization, the so-called postmetallocenes, which includes α-iminocarboxamide-nickel(II) catalysts have attracted a great deal of attention because of many valuable features such as the copolymerization of α-olefins with polar monomers. In this paper, the combinatorial synthesis and evaluation of α-iminocarboxamide-nickel(II) catalysts are discussed for their roles in the discovery of a highly active catalyst and elucidation of its structure-activity relationship. The combinatorial optimization of each reaction condition was performed, then a combinatorial library of α-iminocarboxamides with systematically modified substituents was constructed by amidation of α-keto acid chlorides and subsequent imination of α-keto carboxamides in parallel fashion. As a result, 87 analytically pure α-iminocarboxamide ligands were successfully synthesized. α-Iminocarboxamide-nickel(II) catalysts were prepared from the synthesized α-iminocarboxamide ligands. The catalysts' activities for polymerization of ethylene and copolymerization of ethylene and 5-norbornen-2-ol were evaluated. Results of the present study revealed 9 novel active catalysts for ethylene polymerization and 7 novel active catalysts for copolymerization of ethylene and 5-norbornen-2-ol. It should be noted that the best catalysts for ethylene polymerization and for copolymerization in the present study showed higher activities compared to the known active catalyst. Polymerization activities of the catalysts varied dramatically according to the combination of substituents on the α-iminocarboxamides.     

Preclinical antitumor activity of 5-aza-2′-deoxycytidine agains human head and neck cancer xenografts

Summary The antitumor activity of 5-aza-2-deoxycytidine (5-aza-dCyd), a nucleoside analog, was established in human head and neck cancer xenografts, transplanted in nude mice. A significant response was noted in 3 of 5 lines, when the drug was injected intraperitoneally at a maximum tolerated dose of 2 mg/kg every four days for three doses. In two most sensitive lines 1 out of 6 tumors regressed completely. The antitumor activity of the drug may depend on the schedule used, as illustrated by the fact that just one of these two lines appeared to be sensitive when treated with low daily doses (0.25 mg/kg). One of the two sensitive lines also responded to the treatment with low daily doses (0.25 mg/kg). In two lines, 5-aza-dCyd showed equal or better antitumor activity when compared to the conventional drugs known to produce remissions in patients with head and neck cancer (cisplatin, methotrexate, bleomycin, 5-fluorouracil and cyclophosphamide). 5-Aza-dCyd is a drug with potential value in the chemotherapeutic treatment of patients with head and neck cancer.     

Does leucovorin alter the intratumoral pharmacokinetics of 5-fluorouracil (5-FU)? A Southwest Oncology Group study

Purpose and design: We previouslydocumented that there was an associationbetween the intra-tumoral pharmacokinetics(TPK) of 5-FU and response to therapy with5-FU and leucovorin (p < .0001). Since wehave shown that other modulators of 5-FU,such as methotrexate, interferon andneutrexin alter its TPK, it was of interestto determine if the modulating effect ofleucovorin would also alter the tumoral PKof 5-FU. In order to determine the effectof leucovorin on intratumoral 5-FUpharmacokinetics, 23 patients (21evaluable) underwent ¹⁹F magneticresonance spectroscopy ¹⁹F-MRS)twice. The first ¹⁹F-MRS was following5-FU 600 mg/m² alone, and the second¹⁹F-MRS was following by leucovorin500 mg/m² and then 5-FU 600 mg/m². Results: A comparison of theintratumoral 5-FU pharmacokineticsindicated that there was no general effectof leucovorin on the intratumoral half-lifeof 5-FU. In only two of these 21 patientswas the half-life of 5-FU altered, and inboth cases it was decreased by more than20%. Partial responses to 5-FU plusleucovorin therapy were seen only inpatients with a long intratumoral half-life(trapping) of 5-FU (3 PR in 11 patientswith T_1/2 20 minutes, comparedto 0 PR in 11 patients with T_1/2 <20 minutes). There was a statisticallysignificant correlation between tumorresponse and the intratumoral T_1/2 of5-FU, consistent with our prior results ina larger number of patients. However, therewas no statistically significantcorrelation of time-to-progression orsurvival with classification of thepatients into trappers or non-trappers,probably due to the small sample size inthis current study. Conclusion: The data reported hereare compatible with the hypothesis thatleucovorin enhancement of 5-fluorouracilantitumor responses is not mediated by thelevels of 5-FU in tumors, but rather, isdue to the modulation by leucovorin ofcellular metabolic processes that followthe uptake of free 5-FU into the tumorcell. The MRS technique may be useful inselected instances for elucidating thepossible metabolic interactions of drugsin vivo.     

Semi-physiological pharmacokinetic–pharmacodynamic modeling and simulation of 5-fluorouracil for the whole time course of alterations in leukocyte,neutrophil and lymphocyte counts in rats

Abstract

1. We aimed to develop a simple pharmacokinetic–pharmacodynamic (PK–PD) model to predict the onset and degree of severe toxic side effects that severely limit the use of many anticancer agents, such as myelosuppression, in rats.

2. Our PK–PD model consisted of a two-compartment PK model, with one compartment representing proliferative cells and some transit compartments consisting of maturing cells, while the other compartment represented circulating blood cells for the PD model.

3. The semi-physiological PK–PD model effectively captured the features of myelosuppression and the degree of the off-target toxicities observed after 5-fluorouracil (5-FU) chemotherapy, and helped simultaneously simulate the whole time course for alterations in leukocyte, neutrophil and lymphocyte counts after 5-FU treatment in rats. Interestingly, by plotting the nadir period of leukocyte, neutrophil and lymphocyte counts as determined by PK–PD analytical simulation curves against the area under the plasma 5-FU concentration–time curve (AUC_0–∞) after intravenous administration of 5-FU, a linear relationship was inferred, with r^2?=?0.989, 0.877 and 0.956, respectively.

4. The semi-physiological PK–PD model is a valuable tool for evaluating a variety of novel cancer chemopreventive agents or emerging therapeutic strategies that are difficult to address in humans.     

The quest for the treatment of cognitive impairment: α7 nicotinic and α5 GABAA receptor modulators

Age, age-related pathologies, certain psychiatric disorders, head traumas and other conditions are characterised by an impairment of cognitive functions. Cognition is a complex process involving a large number of neurotransmitters that can modulate, positively or negatively, learning and memory; therefore, their receptors may represent suitable targets to develop cognition-enhancing drugs. Among others, the α₇ nicotinic cholinergic receptor and the α₅ GABA_A receptor are emerging as attractive targets for developing therapeutics in this field. The important role of α₇ nicotinic receptors has been proven thanks to the discovery of α₇-selective agonists, such as GTS-21 and AR-R17779, which has stimulated the synthesis of a large number of new compounds, some of which are in clinical trials. The observation that the classical tranquilliser benzodiazepines (agonists that potentiate GABA_A receptor functions), are amnesic, while inverse agonists (that attenuate the functions of the same receptor) improve cognitive tasks, stimulated the search for modulators mainly directed toward the α₅-containing GABA_A receptor, which seems at present the most important GABA_A receptor subtype involved in cognitive processes. This article reviews the patents on modulators of α₇ nicotinic acetylcholine and GABA_A receptors disclosed during the period 2000 – 2006.