Studies on the chemistry, antitumor activity, and pharmacology of ethyl di-(2,2-dimethyl)ethylenamido phosphate (AB-163)

AB-163, a new alkylating agent containing the 2,2-dimethylaziridine moiety, was found to be active against a number of transplanted and virus-induced tumor systems in mice. This compound hydrolyzes in water at 37 C. The hydrolysis product was isolated and identified as ethanol and amino-tert-butyl phosphate. The compound was shown to react with the model nucleophile 4-(p-nitrobenzyl) pyridine (NBP) comparably to previously studied alkylating agents. The intravenous LD₅₀ was 198 mg/kg and the intraperitoneal LD₅₀ was 159 mg/kg in ICR/Ha male mice. In mice carrying Ehrlich ascites tumor (E-2), 30 mg/kg of AB-163 resulted in 95% tumor inhibition. In Sarcoma-180 inoculated mice, 15 mg/kg caused a 20–30% apparent cure rate and a 62% tumor inhibition of the animals having tumors. Against Adenocarcinoma 755, 40 mg/kg exhibited a 60% cure rate and 50% tumor inhibition of the animals with tumors. Leukemia L1210 treated on days 1–11 was cured in 20–30% of the animals receiving 30 mg/kg of AB-163 and there was a 76–170% increase in survival time in the remaining animals. In animals infected with Friend virus, a 40 mg/kg dose resulted in 65% reduction of splenic weight as compared to controls. Studies in dogs indicated that the main toxicity is hematopoietic depression. Terminally, depression of liver functions was observed. High doses produced central nervous system effects which manifested themselves in loss of appetite, vomiting, increased salivation, lethargy, and convulsions.     

Phase I studies of porfiromycin (NSC--56410) in solid tumors.

Porfiromycin was given to a group of patients with a variety of solid tumors. Of 114 patients admitted to the study, 103 yielded evaluable data. The following dosage schedules were used to determine the toxicity of porfiromycin when given in multiple doses by intravenous injection: 0.2 mg/kg x 5 days, 0.3 mg/kg x 5 days, 0.35 mg/kg x 5 days, 0.4 mg/kg x 5 days, 0.24 mg/kg x 10 days and 0.6 mg/kg weekly. Toxic effects noted were mainly leukopenia, thrombocytopenia, and, when injected paravenously, local tissue necrosis. Biological effects were noted at all dosage levels and were more severe at the higher dosages. The data suggest that profiromycin administered intravenously at a dose of 0.35 mg/kg daily for 5 days results in moderate hermatological toxicity and clinical evaluation in a Phase II study at this dosage level is indicated.     

Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models.

An analysis of dose and schedule dependence of calcium leucovorin rescue during high-dose methotrexate therapy of ascitic forms of l1210 leukemia and Sarcoma 180 is reported. Schedules with very delayed "low-dose" leucovorin rescue following lethal doses of methotrexate were highly effective in preventing toxicity and achieved a pronounced antitumor effect in both ascites tumor models. Best results were obtained on a schedule of methotrexate (400 mg/kg s.c.) followed 16 to 20 hr later by calcium leucovorin (12 mg/kg s.c.) given once every 2 hr for a total of 5 doses. Progressive increases in the calcium leucovorin dosage on any schedule reduced both toxicity and the antitumor effect of methotrexate in each model. Following a single course of therapy, essentially no toxicity was observed, and the antitumor effects were 2-fold (L1210 leukemia) and 4-fold (Sarcoma 180) greater than a single, maximally tolerated dose (24/kg s.c.) methotrexate alone. An increase in the methotrexate dosage to 800 mg/kg s.c. with or without an increase in calcium leucovorin dosages on the same schedule did not appreciably increase the antitumor effect observed. Two courses of high-dose methotrexate (400 mg/kg s.c.) with leucovorin rescue (24 mg/kg s.c. 16, 20, and 24 hr after drug) given with an 8-day interval between courses doubled the total antitumor effect in each model with no substantial increase in toxicity and gave long-term survivors with Sarcoma 180. The results, overall, are in close agreement with prior prediction for schedule and dose dependence made on the basis of related pharmacokinetic and biochemical studies in murine tumor models reported from this laboratory.     

Phase II study of PALA and AMSA in advanced renal cell carcinoma

Ninety-two evaluable patients with measurable renal cell carcinoma participated in a phase II trial of PALA (1500 mg/m2/day for 5 days every 3 weeks) versus AMSA (120 mg/m2 every 4 weeks). No complete responses occurred; objective partial response rates were 5% for PALA and 3% for AMSA. Treatment did not influence survival, but ambulatory patients survived longer than did nonambulatory patients. Mucocutaneous and acute gastrointestinal toxicity occurred with PALA, while hematologic toxicity predominated in AMSA treatments. At these schedules neither drug has significant single-agent activity in renal cell carcinoma.     

Testicular cytotoxicity of intravenous methotrexate in rats

Although the testicular cytotoxicity of methotrexate has been evaluated in the rat, previous models have utilized routes other than the intravenous one, and have generally employed multiple-dose regimens. In this report, we describe testicular toxicity in the Sprague-Dawley rat following a single intravenous bolus of methotrexate (0-700 mg/kg body weight [BW]), with necropsy 56 days later. Testicular toxicity was evaluated qualitatively by histology and quantitatively by testicular weight, sperm head count, modified Johnsen score, repopulation index, and epididymal index. Effects of methotrexate on heart, lung, liver, and kidney histology were evaluated qualitatively. Oligospermia occurred at low and intermediate dosages of methotrexate, but testicular atrophy was not observed. LD₅₀ at day five for methotrexate appears to be approximately 300 mg/kg BW using this regimen. This model will facilitate the study of techniques to avoid drug-induced testicular damage. © Wiley-Liss, Inc.     

A comparative study of PALA, PALA plus 5-FU, and 5-FU in advanced breast cancer

Sixty-three patients with Stage IV breast carcinoma refractory to standard combination chemotherapy agents such as 5-fluorouracil (5-FU) were entered into a study to determine the efficacy of a multiple dose schedule of N-(phosphonacetyl)-L-aspartic acid (PALA) and whether the addition of PALA improves the therapeutic efficacy of 5-FU. Patients were randomized to receive either PALA, 800 to 1000 mg/m2 per day for 5 days every 2 weeks; or PALA + 5-FU, 400 mg/m2 per day for 5 days, and 300 mg/m2 per day for 5 days every 28 days, respectively. The PALA alone arm of the study was closed after 20 patients had been treated and was replaced by 5-FU, 300 to 400 mg/m2 per day for 5 days every 21 days. Overall response rates were 5% for PALA alone, 28% for PALA + 5-FU, and 14% for 5-FU alone. All patients who responded to PALA + 5-FU or 5-FU alone had received prior therapy in which 5-FU was part of the combination chemotherapy program and were considered refractory to this drug. Toxicity affected the gastrointestinal tract but was tolerable in all three arms of the study. Myelosuppression was negligible for PALA and PALA + 5-FU and moderate for 5-FU. The authors concluded that PALA + 5-FU was superior to PALA alone in the therapy of these heavily pretreated patients. PALA alone had marginal efficacy. In view of its low hematologic toxicity, PALA + 5-FU may be combined with more myelosuppressive drugs. Additional studies are necessary to ascertain whether PALA + 5-FU is therapeutically superior to a full-dose schedule of 5-FU.     

Phase I clinical trial of orally administered 4-demethoxydaunorubicin (idarubicin) with pharmacokinetic and in vitro drug sensitivity testing in children with refractory leukemia

Fifteen children with acute leukemia in relapse, refractory to conventional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms of dose-limiting toxicity, affecting the majority of patients at all levels of idarubicin dosage. Two patients who had received total-body irradiation for bone marrow transplantation developed life-threatening gastrointestinal toxicity suggestive of a radiation "recall" phenomenon. Echocardiographic evidence of depressed cardiac function, without clinical symptoms or signs, was noted in six of 11 patients, although the changes were judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and its metabolite, idarubicinol, accumulated during the 3 days of therapy. Among the five patients with acute nonlymphoblastic leukemia whose cells were tested for drug sensitivity in vitro, the idarubicin concentration resulting in 50% inhibition (IC50) of cluster and colony formation ranged from 1.6 x 10(-10) M to 5 x 10(-7) M. There was no obvious relationship between the IC50 for idarubicin and that for epirubicin or daunorubicin. Oral idarubicin produced definite antileukemic effects, clearing blast cells from the circulation in 13 of the 14 evaluable patients. Future studies should define an optimal dose schedule to circumvent the limiting gastrointestinal complications associated with this agent.     

Phase I clinical and pharmacokinetic study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide in children with cancer

Forty-one pediatric patients with advanced cancer (24 with acute leukemia and 17 with diverse solid tumors) received 74 courses of therapy with a new chemotherapeutic agent, 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA: NSC 249992). Treatments were given by slow i.v. injection daily for five days every two to three weeks. In patients with leukemia: (a) dosages were escalated from 1.3 to 150 mg/sq m/day; (b) toxicity in the form of stomatitis, vomiting, and phlebitis occurred at dosage levels of 125 to 150 mg/sq m/day; and (c) oncolytic effects were observed in 13 of 24 patients. In patients with solid tumors: (a) dosages were escalated from 5 to 50 mg/sq m/day; (b) toxicity (stomatitis, myelosuppression, and phlebitis) occurred at the dosage level of 50 mg/sq m/day; and (c) no oncolytic responses were noted. Serum concentrations of total and free AMSA were assayed by a fluorescence technique and declined in a biphasic manner with free AMSA declining more rapidly than total AMSA. Dosages of greater than 100 mg/sq m/day were required to maintain serum concentrations of total and free AMSA greater than 0.2 microM for the entire five-day schedule. The results suggest that maximum tolerated dosages of AMSA may differ in children with leukemia and solid tumors; however, hematopoietic toxicity could not be fully evaluated in the patients with leukemia. AMSA has clear antileukemic activity that warrants future Phase II trials.     

Phase I study of N(1),N(11)-diethylnorspermine in patients with non-small cell lung cancer.

PURPOSE: Polyamines are essential for tumor growth; consequently, agents that interfere with their metabolisms have been developed as antineoplastic agents. Diethylnorspermine (DENSPM) is one such agent. A focused Phase I clinical trial in patients with advanced non-small cell lung cancer was undertaken. EXPERIMENTAL DESIGN: Twenty-nine patients were treated with DENSPM using a dosing schedule of once daily for 5 days. Doses ranged from 25 mg/m(2)/day to 231 mg/m(2)/day. RESULTS: The dose-limiting toxicity was determined to be gastrointestinal including asthenia, abdominal cramps, diarrhea, and nausea. The maximal tolerated dose was 185 mg/m(2)/day for 5 days. At drug dosages for which it was possible to estimate, serum half-life ranged from 0.5 to 3.7 h without apparent dose dependence. Maximal serum concentrations increased with dosage. However, the increase was greater than the proportional increase of the administered dose. There were no objective disease responses observed during the Phase I trial. CONCLUSIONS: The results of the Phase I clinical trial suggest that DENSPM can safely be administered to patients with minimal toxicity. Furthermore, the observed dose-limiting toxicity is unique to DENSPM, thus underscoring the potential for DENSPM to be a suitable agent for chemotherapy in combination with agents possessing different spectrums of toxicities.     

The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug CI-941 in the mouse: a guide for rational dose escalation in patients

Summary CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses >20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD₁₀ value of 20 mg/kg (95% confidence limits; range, 19–21 mg/kg) and an LD₅₀ value of 22 mg/kg (95% confidence limits; range, 21–23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD₁₀ to the LD₁₀ (20 mg/kg). The drug was rapidly cleared from the plasma (250–400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC=110 M x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC=277 M x min). Despite 80%–84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%–18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD₁₀ in the mouse) of 5 mg/m² CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 M x min, is proposed.     

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-l-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m² given on day 1, followed 24 h later by MMPR 150 mg/m², and escalating doses of 5-FU from 1625 to 2600 mg/m² by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m². Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m², MMPR 150 mg/m², and 5-FU 2300 mg/m² by continuous infusion over 24 h.     

Prevention by chitosan of myelotoxicity, gastrointestinal toxicity and immunocompetent organic toxicity induced by 5-fluorouracil without loss of antitumor activity in mice.

We examined the antitumor activity and side effects (myelotoxicity, immunocompetent organic toxicity and gastrointestinal toxicity) of combined treatment with the cancer chemotherapy drug 5-fluorouracil (5-FU) and dietary fiber chitosan in sarcoma 180-bearing mice. 5-FU (12.5 mg/kg x 2/day) plus chitosan (150, 375 and 750 mg/kg x 2/day) inhibited the tumor growth as well as 5-FU alone. Chitosan (150 and 750 mg/kg x 2/day) blocked the reduction of blood leukocyte number caused by 5-FU administration, and it prevented the injury of the small intestinal mucosa membrane and delayed the onset of diarrhea induced by 5-FU. Furthermore, chitosan (750 mg/kg x 2/day) prevented the reduction of spleen weight induced by 5-FU in sarcoma 180-bearing mice, and the reduction of lymphocyte and CD8+ T cell numbers induced by 5-FU was also prevented by the oral administration of chitosan (750 mg/kg x 2/day) in C57BL/6 mice. Chitosan (150 and/or 750 mg/kg x 2/day) reduced the 5-FU incorporation into RNA fractions of small intestine and spleen without affecting the 5-FU incorporation into the tumor in sarcoma 180-bearing mice. These findings suggest that prevention of the 5-FU side effects by chitosan might be partly due to the selective inhibition of 5-FU uptake into the small intestine and spleen, resulting in the reduction of immune function toxicity, myelotoxicity and gastrointestinal toxicity of 5-FU. Therefore, it is concluded that the combination of chitosan and 5-FU might be useful for the prevention of side effects such as gastrointestinal toxicity, immunotoxicity and myelotoxicity caused by 5-FU.     

N-(phosphonacetyl)-l-aspartate and calcium leucovorin modulation of fluorouracil administered by constant rate and circadian pattern of infusion over 72 hours in metastatic gastrointestinal adenocarcinoma

Background:We have reported thatN-(phosphonacetyl)-l-aspartic acid (PALA) 1266 mg/m² cansafely be given 24 hours prior to the start of a 72-hour infusion offluorouracil (FUra) and leucovorin (LV) at doses of 2000 and 500mg/m²/day. Since inhibition of aspartate carbamoyltransferase(ACTase) activity was evident 4 hours post PALA, we wished to evaluatePALA given 1 hour prior to FUra. Further, we studied the toxicity andpharmacokinetics with FUra given by either fixed-or variable-rateinfusion. Patients and methods:Twenty-seven patientswith gastrointestinal tract adenocarcinomas were treated with PALA 1266mg/m²/15 min followed by a 72-hour infusion of FUra and LV (1750 & 500 mg/m²/day) given by fixed- orvariable-rate (peak at 4:00 A.M.). Results:Clinicaltoxicity was similar in two consecutive cycles in 17 patients receivingfixed- and variable-rate infusion at the same FUra dose. Overall, grade3 stomatitis and hand-foot syndrome occurred in 12% and 4%patients receiving fixed- and in 16% and 10.5% of patientsreceiving variable-rate infusions. Six of 24 evaluable patients(25%) had a partial response. The profile of FUra plasma levels(Cp) over a 24-hour period during fixed- and variable-rate infusionswere strikingly different, but the average Cp and area under theconcentration-time curves were comparable. ACTase activity wassignificantly decreased at 4 and 24 hours after PALA(12% and 18% of baseline;P < 0.001), but enzyme activity had recovered to40% by 72 hours. Conclusions:This regimen wasactive and well tolerated with similar toxicities with FUra given byeither fixed- or variable rate infusion. PALA 1266 mg/m²significantly inhibited ACTase activity for at least 24 hours.     

2-(α-羟基戊基)苯甲酸钾盐的急性毒性和致突变作用研究

目的:研究2-(α-羟基戊基)苯甲酸钾盐(dl-PHPB)的急性毒性及致突变性。方法:急性毒性试验采用Bliss法,昆明小鼠分为5组,每组10只,雌雄各半,分别按256.0、286.3、320.0、357.8、400.0、447.2 mg/kg静脉注射dl-PHPB,观察注射后至给药后14 d动物的毒性反应性质及程度,计算半数致死剂量(LD₅₀)及95%可信限;Ames试验采用平板掺入预培养法,选用鼠伤寒沙门氏菌株TA97、TA98、TA100和TA102,每皿0.5～5 000.0 μg浓度范围内,检测加和不加S9条件下对Ames菌的致突变性;微核试验采用雄性昆明小鼠,分为3组,每组6只,分别按23.3、70、210 mg/kg单次静脉注射dl-PHPB,注射后24 h计数骨髓嗜多染红细胞微核率(MNPCEs);体外染色体畸变试验在加和不加S9条件下,检测11.0~88.0 μg/mL dl-PHPB对CHL细胞染色体畸变率的影响。结果:小鼠静脉注射dl-PHPB后,各剂量动物出现一过性呼吸急促、自发活动减少、俯卧少动等症状,随剂量增加至≥320.0 mg/kg时,部分动物出现濒死症状,并在给药后2~30 min内死亡,死亡率随剂量的增加而增加,256.0~447.2 mg/kg 6个剂量组死亡率依次为0、0、10%、30%、70%、100%。未死亡动物在给药30 min后逐渐恢复正常。14 d观察期期间动物未见其他异常。其LD₅₀为373.3 mg/kg,95%可信限为355.6～392.0 mg/kg;Ames试验结果显示,在每皿0.5～5 000.0 μg浓度范围内未引起4种测试菌株回复突变数增加;微核试验结果显示,dl-PHPB在23.3~210.0 mg/kg范围内,各组动物MNPCEs均低于4‰;CHL细胞体外染色体畸变试验中,dl-PHPB在 11.0～88.0 μg/mL浓度范围内致CHL细胞染色体畸变率<5%。结论:在本实验条件下,小鼠静脉注射dl-PHPB的LD₅₀为373.3 mg/kg,致突变性3项试验均为阴性结果。     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphon-acetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma

Purpose: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma.Patients and methods: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m² i.v. 15-minute infusion followed by methotrexate 200 mg/m² i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m² i.v. push on day 2. Folinic acid was given at 15 mg/m² p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks.Results: Thirty patients with advanced chemotherapy-naive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27–72); median PS 1 (0–2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients.Conclusions: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.     

Fec (Fluorouracil, epirubicin, cyclophosphamide) plus granulocyte macrophage-colony-stimulating factor (gm-csf) in advanced or inflammatory breast-cancer - a dose-finding study

Seven patients with inflammatory and 11 with metastatic breast cancer were treated with high dose FEC chemotherapy plus GM-CSF; 5-fluorouracil and cyclophosphamide were administered at 500 mg/m2/iv/day 1, epirubicin at three dose levels: 100 mg, 120 mg and 140 mg/m2/iv/day 1 every three weeks (six patients per level). GM-CSF was administered at a dosage of 5 mg/kg/sc from day 5 to 12 of each cycle. The overall response rate was 83% (95% CI: 66%-100%) with 22% complete response. The median response duration for patients with metastatic disease was 7 months (range: 4-10). The hematological toxicity was moderate but reversible due to GM-CSF rescue; mucositis represented the dose limiting toxicity. In conclusion, the increase of dose intensity resulted in a higher response rate but not longer response duration, which must be taken into account when administering high-dose chemotherapy with growth factor rescue.     

Bolus/infusional 5-fluorouracil and folinic acid for metastatic colorectal carcinoma: are suboptimal dosages being used in the UK?

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.     

Experimental studies on subrenal capsule assay using cyclosporin A treated mice--the optimal treatment schedules of CsA and anticancer agents (mitomycin C and 5-fluorouracil)

We studied fundamentally subrenal capsule assay, using human tumor specimens (breast, gastric and colon cancers) serially transplanted in nude mice. When cancer anticancer agents such as mitomycin C (MMC) and 5-fluorouracil (5-FU) were injected into immunocompetent mice treated with various dosages of cyclosporin A (CsA) after tumor implantation, optimal schedule of each drug was examined on the points of effects and toxicity against host mice. The following results were obtained. Control groups were set up as immunocompetent mice which treated daily with 60 mg/kg CsA from day 1 after tumor implantation. Optimal treatment schedule was judged as MMC 3 mg/kg i.v. injection on day 1 following by daily 60 mg/kg CsA treatment, and 5-FU was injected 25 mg/kg subcutaneous injection every day from day 1 without CsA treatment, each schedule showed an appropriate anti-tumor activity profiles against implanted tumor xenografts, and had less toxicity to the hosts.     

Biodistribution and toxicity of photoproducts of merocyanine 540

Summary Light-activated merocyanine 540 (pMC540) has been shown in our earlier studies to be effective against certain types of tumor cells and viruses, including human immunodeficiency virus (HIV-1). To test the potential extracorporeal and systemic use of pMC540, its toxicity was investigated in DBA/2 mice, pigs, and dogs. The lethal dose in DBA/2 mice after an i.p. injection was 370 mg/kg, and the 50% lethal dose (LD₅₀) was 320 mg/kg; however, following i.v. administration, the lethal dose and the LD₅₀ dose were 240 and 160 mg/kg, respectively. Tritium-labeled MC540 was used to study the biodistribution of pMC540 in DBA/2 mice. Almost 70% of the injected radioactivity was excreted within 6 h of injection. After 1 week, the pMC540 was almost completely cleared, with only 1.89% of the activity remaining, and had a plasma half life of 23 h. Pigs injected with an accumulated dose of 10 mg/kg and followed for a period of 30 days did not show adverse signs of toxicity as monitored by SMAC-28 analysis, CBC profile, and blood-coagulation studies. A dog injected with a single dose of 20 mg/kg showed induction of the hepatic enzymes glutamic oxaloacetic transminase (AST) and glutamic pyruvic transaminase (AST); however, serum levels of gamma-glutamyl transpeptidase (GGT) remained unchanged. The data presented herein may serve to identify certain drug-dose limitations in the systemic use of pMC540. Abbreviations: pMC540; p-³H-MC540; AST; ALT; CPK; GGT     

Inhibitory effects of Candida albicans extracellular polysaccharides on mouse sarcoma 180

Extracellular glycoprotein produced by Candida albicans in chemically defined medium was used to treat solid Sarcoma 180 tumor cells implanted subcutaneously in Swiss female mice. Neither toxicity nor skin ulcerations surrounding the tumors was observed. Significant tumor inhibition was obtained using different methods to evaluate treatment effectiveness. Comparison of tumor weights after a single treatment (400 mg/kg, ip) on various days after transplantation indicated significant inhibition with a 10–80% regression rate. Multiple doses (800–2,000 mg/kg, ip) regressed 60–90% of all tumors. Subsequent dosage experiments showed an increased percentage of survivors for all treated groups and a significant decrease in tumor size. Studies of the glycoprotein material indicated that it was immunologically active.