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Background:Identification and development of drugs that can effectively modulate the therapeutic efficacy and toxicity of chemotherapy remain an unmet challenge. We evaluated the effects of Se-methylselenocysteine (MSC) on the toxicity and antitumour activity of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan in animal models.Methods:Cyclophosphamide, cisplatin, and oxaliplatin were administered by a single i.v. injection and irinotecan by i.v. weekly × 4 schedules. For the combination, MSC was administered daily via the oral route for 7 days in mice and daily for 14 days in rats before and concurrent with drug administration.Results:Se-methylselenocysteine significantly protected against organ-specific toxicity induced by lethal doses of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan. These include diarrhoea, stomatitis, alopecia, bladder, kidney, and bone marrow toxicities. Protection from lethal toxicity by MSC was associated with enhanced antitumour activity in rats bearing advanced Ward colorectal carcinoma and in nude mice bearing human squamous cell carcinoma of the head and neck, FaDu, and A253 xenografts.Conclusions:Se-methylselenocysteine offers selective protection against organ-specific toxicity induced by clinically active agents and enhances further antitumour activity, resulting in improved therapeutic index. These data provided the rationale for the need to clinically evaluate MSC as selective modulator of the antitumour activity and selectivity of anticancer drugs. [ABSTRACT FROM AUTHOR]

There is a need for chemotherapy regimens active against anthracycline- and taxane-refractory breast cancer. Data from preclinical and pilot studies performed at Roswell Park Cancer Institute (RPCI) suggested that when irinotecan (IRN) is given with 5-fluorouracil (5-FU) efficacy is affected by the sequence of drug administration. Pretreatment with IRN 24 h before 5-FU increased the number of tumor cells in S-phase and the antitumor activity in a preclinical system. These data provided the rationale for the evaluation of IRN and capecitabine, a 5-FU prodrug, sequentially administered in patients with metastatic breast cancer. The main objective of the study was to determine the MTD and identify dose-limiting toxicities (DLTs) of capecitabine and IRN. Additionally, the degree of accumulation of cells in S-phase in tumor biopsies obtained at 24 h after the first dose of IRN was measured in consenting patients. Metastatic breast cancer patients who experienced disease progression after at least one (taxane or anthracycline based) chemotherapy regimen and an expected survival of at least 3 months and ECOG performance status 0–2 were eligible. Twelve patients were enrolled and treated. The starting doses were IRN 80 mg/m2 given over 90 min on days 1, 8, 22, 29, and capecitabine 1,500 mg/m2/day given days 2–15 and 23–36. Evaluation for response was performed after the first cycle. Sequential tumor biopsies were performed on five patients. The first three patients treated exhibited modulation in cyclin A index on tumor biopsy as defined by the study, defining the modulatory dose of IRN as 80 mg/m2. Overall, 4/5 biopsies showed modulation. Dose Limiting Toxicities (DLTs) were assessed during the first cycle of therapy. Two DLTs (Grade 3 nausea vomiting and dehydration; grade 3 pneumonia, hypoxia, hypotension) were seen at dose level 2 of capecitabine (2,000 mg/m2/day) and the first cohort was expanded. There were no DLTs for patients treated at DL 1. No grade 3–4 toxicities occurred at DL 1. Seven patients were evaluable for response following one cycle of treatment (partial response 1, stable disease 4, progressive disease 2) Of the five inevaluable patients, two experienced DLT, one received 50% of the planned capecitabine dose, one progressed prior to evaluation, and one withdrew consent. IRN 80 mg/m2 days 1, 8, 22, 29 in combination with capecitabine 1,500 mg/m2/day in divided dose days 2–15 and 23–36 has an acceptable toxicity profile and resulted in modulation of S-phase in 4/5 specimens examined. Further studies of the activity of this combination and modulatory effect of IRN are warranted. [ABSTRACT FROM AUTHOR]

Recent data suggest that expression of the membrane P[SUB170]-glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. [ABSTRACT FROM AUTHOR]

A phase I and pharmacokinetics study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer. Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, and 350 mg/m2 of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at 350 mg/m2 UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously untreated patients, UFT at 350 mg/m2 was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m2) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide interpatient variations. Plasma levels of 5-FU (Cmax 1.4 +/- 1.9 microM) were comparable to those achieved with protracted venous infusions, and folate levels (Cmax 6.1 +/- 3.6 microM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs. [ABSTRACT FROM AUTHOR]

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (> 200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified. [ABSTRACT FROM AUTHOR]

The effect of N-(3,4-dimethoxyphenyl) N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 microM as compared with 10 microM verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic. [ABSTRACT FROM AUTHOR]

A total of 24 patients with advanced colorectal adenocarcinoma were entered into a phase I-II study of 5-fluorouracil (5-FU) and cisplatin, 21 of whom had previously received 5-FU. The starting dose of cisplatin was 20 mg/m2 diluted in 1000 cc normal saline, given over 20 h daily for 5 days, together with 600 mg/m2 5-FU diluted in 1000 cc fluid, given simultaneously over 20 h daily for 5 days. This regiment was given every 4 weeks. The dose-limiting toxicity was renal and cumulative. All 24 patients were evaluable for toxicity. Of 12 patients on the above-mentioned starting dose, 8 underwent a cisplatin dose reduction to 15 mg/m2 due to a progressive decrease in creatinine clearance following the second or third course of treatment. Of 12 patients who started cisplatin at 15 mg/m2 and 5-FU at 600 mg/m2, 11 were maintained at this dose. A WBC nadir count of less than 2000/mm3 was seen in four patients. Thrombocytopenia occurred in three patients who received 15 mg/m2 cisplatin and 600 mg/m2 5-FU. In all, 21 of the 24 patients had objectively measurable disease and were also evaluable for response as follows: 1 complete response, 2 partial responses, 1 case of stable disease, and 17 patients with progressive disease. [ABSTRACT FROM AUTHOR]

Concurrent administration of thymidine (TdR) has been shown to increase the antitumor activity of 5-fluorouracil (5-FU) in various experimental models. The clinical response rate, side-effects, and toxicity of 5-FU and TdR were evaluated in 27 patients with advanced colorectal carcinomas. Each 6-day treatment course consisted of an IV loading dose of TdR (405 mg/kg, over 30 min), followed by continuous IV infusions of 5-FU (7.5 mg/kg per day for 5 days), and TdR (216 mg/kg per day for 6 days); courses were repeated every 4 weeks. The overall partial response rate was 4.5%, or 16.7% in patients with no prior 5-FU chemotherapy. Short-lived stable disease was seen at an overall rate of 27.3%, half of these patients with prior 5-FU chemotherapy. Myelotoxicity occurred in 64% of the patients, but this was dose-limiting in only 20%. Gastrointestinal and neurological symptoms were mild and infrequent. There was one case of treatment-related death due to sepsis secondary to leukopenia. It is concluded that the concurrent IV administration of 5-FU and TdR does not improve the response rate over that obtained with 5-FU alone. [ABSTRACT FROM AUTHOR]

A two-step procedure for releasing cells from solid tumors has been applied to specimens of human melanoma, sarcoma, lung, colon, and breast carcinoma. The first population released mechanically has been compared with the population subsequently released enzymatically in tests of dye exclusion, ribonucleoside triphosphate pool sizes, intactness of DNA, and clonogenicity in soft agar. While greater numbers of dye-excluding cells are released in the enzymatic step, and these cells have higher ribonucleoside triphosphate pools and more intact DNA, both populations contain clonogenic cells in approximately equal numbers. Several semisolid media were employed in tests of clonogenicity, and all methods employing an agar underlayer appeared satisfactory and approximately equivalent in cloning efficiency. The methyl cellulose upper layer system facilitated implanting of pooled colonies into nude mice, which resulted in growth in the nude host and marked increase in cloning efficiency when the cells were replanted into soft agar-methyl cellulose plates. A comparison of four different areas of individual tumor specimens was made with cells released enzymatically and measuring cell yield, dye exclusion, ATP pool size, and uptake and metabolism of 5-fluoropyrimidines. Only relatively small variations were seen from one area to the next, with trypan blue exclusion exhibiting the least variation, and metabolism of fluorinated pyrimidines showing the most. [ABSTRACT FROM AUTHOR]

Aim: We previously showed SLM reduces CPT-11 toxicity and improves activity at plasma levels ≥ 1200 ng/mL Se in animals. Our aim was to characterize SLM PK and design a dose regimen to achieve this target in pts.Method: 13 refractory solid tumor pts enrolled in a Phase I trial of SLM (2200ug Se as SLM PO QD) started 1 wk before dose escalated CPT-11. Intensive plasma PK of Se on d8 of cycle 1 and troughs during therapy. CPT-11 and metabolite (SN38, SN38G) PK determined wks 1 and 4. PK analyzed by compartmental modeling.Results: Se accumulation was slow: 4-6 wks to achieve steady state. Mean (SD) CLt/F and T1/2 of Se after SLM was 0.12 (0.05) L/h and 183 (94)h. CPT-11 biliary index, BI=AUC(CPT11.SN38/SN38G), associated with GI toxicity, was 85% lower after 4 wks SLM vs. wk 1. Simulations were used to design regimens to achieve the 1200 ng/mL target within 7d, before CPT-11. These candidate SLM strategies are being formally tested in an ongoing Phase I trial of fixed dose CPT-11 and dose escalated SLM based on toxicity and[Se]. 16 pts have enrolled: 4/6 achieved the 1200 ng/mL target within 7d after a loading dose of 4000ug SLM BID x7d; 2/6 subjects were within 23 and 14% of the target. Maintenance doses of 3200ug QD maintained 5/6 patients > 1200 ng/mL for 3 - 4 months.Conclusion: SLM demonstrated a long T1/2, significant and slow accumulation, and may reduce CPT-11 GI toxicity by altering BI. The use of modeling, simulation, and a 'learn and confirm' approach to the development of SLM as a therapeutic has improved the ability to evaluate this novel compound rapidly and efficiently.Clinical Pharmacology & Therapeutics (2005) 79, P31–P31; doi: 10.1016/j.clpt.2005.12.114 [ABSTRACT FROM AUTHOR]