The effect of single versus split doses of diethylnitrosamine on the induction of gamma-glutamyltranspeptidase-foci in the livers of adult and juvenile rats

The induction of gamma-glutamyltranspeptidase (GGT)-foci bysingle and by split doses of diethylnitrosamine (DENA) was evaluatedin the livers of juvenile and young adult male, Sprague-Dawleyrats. A single dose of DENA was administered at either 32, 41,46, 52 or 56 days of age and followed by a promoting regimenof sodium phenobarbital in the drinking water. In 32 day oldrats, DENA resulted in a higher incidence of GGT-foci/cm³ thanwas observed when it was administered to 41 or 46 day old rats.The same dose of DENA was inactive in 52 or 60 day old rats.In rats initiated with DENA on day 32 of age, starting the phenobarbitalpromotion at 41 days of age resulted in a higher incidence ofGGT-foci than when the phenobarbital treatment was begun at60 days of age. When the dose of DENA was split into five dailydoses of DENA starting on day 32 of age, the incidence of GGT-foci/cm³was equivalent to the single dose given on day 32 of age. However,when the five daily doses were started on 48 days of age, theincidence of GGT-foci/cm3 was less than the five doses of DENAstarted on day 32 of age. Hence, juvenile rats were more sensitiveto both single and split doses of DENA than adult rats. Thedose-response relationship was also determined in juvenile ratsfor a single and for up to 64 daily doses of 3 mg/kg DENA startedon day 32 of age. The dose-response relationship for a singledose of 3 % mg/kg DENA was equivalent to the relationship ofone to 32 daily 3 mg/kg doses. Thus, low daily doses of DENAwere additive when started in juvenile rats. Neither a thresholdnor a plateau was obtained for the dose-response relationshipof DENA initiation of GGT-foci.     

Combination Phase I/II Study of Irinotecan Hydrochloride (CPT-11) and Carboplatin in Relapsed or Refractory Non-Hodgkin's Lymphoma

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecinwhich inhibits topoisomerase I. Phase II studies have demonstratedthat CPT-11 is active against a broad spectrum of neoplasmsincluding intractable non-Hodgkin's lymphoma. An early phaseII study in lymphoma suggested that a schedule of daily infusionsof 40 mg/m²/day for three or five consecutive days is more effectivethan a single infusion of 200 mg/m² every three to four weeks.Carboplatin is also an active agent against lymphoma, and preclinicalstudies have shown that CPT-11 and its active metabolite havea synergistic effect with platinum compounds. To evaluate themaximal tolerated dose (MTD) and the therapeutic efficacy ofCPT-11 in combination with carboplatin in relapsed or refractorynon-Hodgkin's lymphoma, we conducted a combination phase I/IIstudy. The starting dose of CPT-11 was 20 mg/m²/day (days 1through 3 and 8 through 10), and dose escalations of 5 mg/m²/dayincrements were planned, with a fixed dose of carboplatin (300mg/m², day 1). Six of the eight patients receiving both agentsat the starting dose level developed critical toxicities suchas grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8)and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminaseelevation 1/8). Further dose escalation of CPT-11 was halted,and the starting doses were judged to be the MTDs. The responserate (25%, 2/8) to the combination of the MTDs was not superiorto that of CPT-11 alone in a previous phase II study (38%, 26/69),and the MTD of CPT-11 in combination with carboplatin was lessthan half the single-agent dose. We conclude that carboplatinis not recommendable for combination with CPT-11 in lymphomapatients. Other suitable agents for such a combination shouldbe sought.     

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors

BACKGROUND: Paclitaxel is a novel agent with significant activity in severalsolid tumors. Preclinical data suggested that methotrexate priorto pacitaxel would be synergistic. To determine the qualitativeand quantitative toxicity of this regimen we performed a phaseI study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more thantwo prior chemotherapy regimens were given methotrexate intravenouslyon day 1, followed by pacitaxel, as a 24-hour infusion on day2. The starting dose (level ‘0’) was 40 mg/m formethotrexate and 135 mg/m for paditaxel. RESULTS: After achieving a maximum tolerated dose, additional patientswere enrolled with the addition of G-CSF 5 µg/kg/d ondays 4–13. At the starting dose level, dose-limit ingtoxicity consisting of neutropenic fever occurred in 3 of 4patients. At dose level–1, methotrexate 30 mg/m² and paclitaxel110 mg/m² neutropenic fever occurred in 7 of 10 patients duringthe first course. At dose level–2, methotrexate 23 mg/m²and paclitaxel 85 mg/m² neutropenic fever occurred in 1 of 7patients. To abrogate the neutropenia we explored the same combinationwith the addition of G-CSF. Neutropenic fever remained the onlydose-limiting toxicity. At dose level ‘0’ with G-CSF,1 of 7 patients developed doselimiting toxicity. At dose level1 plus G—CSF, methotrexate 40 mg/m² and pacitaxel 170mg/m² dose-limiting neutropenic fever occurred in 4 of 6 patients.Partial responses occurred in 4 of 41 patients entered on thisstudy. Pharmacokinetic data suggested that methotrexate didnot increase pacitaxel levels. CONCLUSION: The combination of methotrexate and paci taxel is feasible,but neutropenic fever, even with the addition of G—CSFprevents further escalations of paclitaxel beyond 135 mg/m²following methotrexate. phase I, methotrexate, paclitaxel, solid tumors     

Resistance of Salmonella typhimurium TA 1535 to O6-guanine methylation and mutagenesis induced by low doses of N-methyl-N'-nitro-N-nitrosoguanidine: an apparent constitutive repair activity

Salmonella tester strains which are reverted by base-pair substitutionmutagens are relatively insensitive to the mutagenic effectsof N-methyl-N-nitroso compounds. One reason for this insensitivityis the ability of these strains to withstand low doses of thesecompounds before they become sensitive to their mutagenic effects.In this report it is shown that mutagenesis induced by treatmentof Salmonella typhimurium TA 1535 with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) in buffer is biphasic with a low sensitivity range atlow doses where little mutagenesis occurs, followed by a highsensitivity range whose onset begins after an apparent thresholddose has been exceeded. Levels of O⁶-methylguanine (O⁶-MeG)in the DNA extracted from the bacteria follow a similar dose-responsecurve suggesting a dependency of mutagenesis on O⁶-MeG. In contrast,levels of 7-methylguanine (7-MeG) in the DNA increase linearlywith dose. O⁶-MeG was undetectable at the lowest dose of MNNGwhereas 7-MeG was readily detectable. Although such resistanceto O⁶-alkylation has been demonstrated in MNNG-pretreated (adapted)E. coli, it has not been reported in unpretreated cells. Whenisolated DNA was treated with MNNG a linear dose-response inthe generation of O⁶-MeG was observed. The lack of O⁶-MeG inDNA isolated from MNNG treated cells after low doses is attributedto a saturable, constitutive repair activity in the bacteria.An attempt to observe the removal of O⁶-MeG from the bacteriaafter exposure to a short challenge dose of N-nitroso-N-methylurea(NMU) followed by a subsequent incubation in buffer was unsuccessful,probably because all the repair occurred within the time necessaryto treat and lyse the cells.     

Multi-day fractionated administration schedule for paclitaxel

PURPOSE: To establish the feasibility of fractionating paclitaxel administrationby utilizing daily one-hour infusions for three, four or fivedays with dose escalating to determine the patterns of hematologicand non hematologic toxicities. PATIENTS AND METHODS: Forty patients received 87 courses of daily fractionated paclitaxelfor three, four or five days; cycles were repeated every 21days. Six patients received concomitant daily cisplatin. Themedian number of cycles delivered per patient was two with arange of one to six. RESULTS: Cumulative doses per cycle ranged from 120 mg/m² to 250 mg/m²with 25% of the cycles delivering 200 mg/m² or more. Ten cycles(11.5%) were associated with dose limiting neutropenia (grade3 [7 cycles]; grade 4 [3 cycles]). No hypersensitivity reactionswere observed and no patient required cytokine support. No patientrequired hos-pitalization. CONCLUSION: Administering paclitaxel on a daily fractioned schedule in anambulatory setting is logistically feasible; does not requirepremedication; is associated with a toxicity pattern similarto single day schedules (e.g. 24-hour or three-hour infusion);is capable of delivering a higher dose per cycle than published96- or 120-hour infusion schedules; and could possibly be escalatedto doses higher than 250 mg/m² in carefully selected patients.The optimal dose rate for five-day multifrac-tionated administrationof paclitaxel is 40 to 50 mg/m²/d or a cumulative cycle doseof 200 to 250 mg/m² and does not require cytokine usage. Addingcisplatin on a fractionated daily schedule may accentuate theneurotoxicity associated with both agents. A prospective comparisonof four-day fractionated vs. four-day continuous infusionalpaclitaxel has been proposed as a randomized study to determineclinical differences in response, dose intensity and toxicity. paclitaxel, schedule-dependent administration     

Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors

BACKGROUND: In a previous phase I study we showed that single-agent cisplatincan be given weekly for six weeks at a dose of 80 mg/m²/wk.It has been suggested that etoposide has synergistic activitywith cisplatin and the drug can be given orally continuously.We therefore performed a phase I study with weekly cisplatincombined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were enteredin the study. Cisplatin was administered in hypertonic saline(NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m²for six weeks combined with daily oral etoposide at a dose of50 mg. At the maximum tolerable dose of cisplatin 75 mg/m²/wkand etoposide 50 mg/m² daily, leukocytopenia and thrombocytopeniawere dose-limiting toxic effects which resulted in frequenttreatment delays. Other toxicities were mild. Finally, a doseof cisplatin 70 mg/m²/wk weeks 1–2–3 and weeks 5–6–7in combination with etoposide 50 mg orally days 1–15 anddays 29–43 combined a high median cisplatin dose intensityof 52.5 mg/m²/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combinationwith oral etoposide. Leuko-cytopenia and thrombocytopenia aredose-limiting toxicities. The schedule will be explored furtherin phase n studies. phase I, cisplatin, etoposide, dose intensity     

O6-Methyguanine levels and histopathological changes in the rat esophagus and liver following single and repeated administration of N-nitrosomethylbenzylamin

In this study we investigated the time course of O⁶-methylguanine(O⁶-meGua) levels and concomitant histo-pathological effectsin the rat esophagus and liver following single and repeateds.c administration of the esophagus-specific carcinogen N-nitrosomethylbenzylamine(NMBA). The primary purpose of this study was to determine ifdifferences in the induction and/or persistence of O⁶-meGuamight account for differences in the tumorigenicity of NMBAobserved with treatment regimens of 0.5 mg/kg/ dose, 3 doses/weekfor 5 weeks (a proven tumorigenic regimen) and 1.67 mg/kg/dose,3 doses/week for 2 weeks (an essentially non-tumorigenic regimen).Results of the single dose experiment indicated that enzymaticactivation of NMBA in the rat esophagus was not dose limited,at least at doses up to and including 5.0 mg/kg. Results ofthe repeated dose experiment demonstrated that the non-tumorigenicNMBA regimen produced significantly higher levels of esophagealO⁶meGua compared with the tumorigenic NMBA regimen. During the2 week treatment period of the non-tumorigenic regimen esophagealO⁶-meGua levels decreased progressively, but remained significantlyhigher than in the tumorigenic regimen. In contrast, the relativelylower O⁶-meGua levels of the tumorigenic regimen remained essentiallyunchanged during the course of treatment At 72 h following conclusionof dosing no O⁶-meGua was detected in the esophagi of rats treatedwith either regimen. Microscopic examinations revealed thatthe non-tumorigenic NMBA regimen produced a marked cytotoxiceffect on the esophageal epithelium, while microscopic esophagealchanges observed with the tumorigenic regimen were generallyless severe. In the liver O⁶meGua was detected in only a fewrats and no remarkable microscopic pathology was observed inthis organ. Together these findings indicate that: (i) abbreviatedNMBA treatment induces tumors in the rat esophagus only at levelsthat induce DNA damage without causing extensive cytotoxicity;(ii) the lack of NMBA tumorigenicity in the rat liver may bedue, at least in part, to the rapid and efficient repair ofO⁶-meGua adducts, coupled with the lack of necrosis and compensatorycell division in this organ.     

A phase I trial of intermittent high-dose {alpha}-interferon and dexamethasone in metastatic renal cell carcinoma

BACKGROUND: Evidence exists that the toxic effects of a-interferon can beameliorated by co-administration of dexamethasone without compromiseof therapeutic efficacy. We therefore conducted a phase I trialto determine the maximum tolerated dose of intermittent interferonwhen combined with oral dexamethasone PATIENTS AND METHODS: Thirty patients with metastatic renal cell carcinoma were enrolled.The starting dose of interferon was 20 million IU/m²/day givenas a subcutaneous injection days 1 to 4 of each 14 day cycle.Dose levels were escalated at increments of 5 million IU/m².Dexamethasone 4 mg was administered orally every 6 hours duringadministration of high-dose interferon. Low-dose maintenanceinterferon, 3 million lU/m²/day, was administered without doseescalation on days 5 to 14 of each cycle. RESULTS: The maximum tolerated dose of intermittent high-dose interferonwas 40 million IU/m²/day. The dose limiting toxicity was fatigue.EEG abnormalities developed in five patients and neuropsychiatricparameters deteriorated significantly in seventeen. CONCLUSIONS: We conclude that co-administration of dexamethasone improvesthe tolerance of intermittent high-dose interferon. The resultsof this trial may be useful in designing high-dose interferonregimens for renal cell carcinoma and other interferon-sensitivediseases. dexamethasone,     

Dose-escalation Study of Oral Etoposide and Carboplatin in Patients with Advanced Lung Cancer

A dose-escalation study of daily etoposide and carboplatin wascarried out on 23 patients with advanced lung cancer using astarting dose of 40 mg/m²/day etoposide given orally for 21days and 250 mg/m² carboplatin given intravenously (IV) on day1. A total of 41 courses were given. Myelosuppression was themajor dose-limiting toxicity. The maximum tolerated dose wasreached at the fourth level with 40 mg/m²/day etoposide for21 days and 400 mg/m² carboplatin on day 1, once every 4 weeks.Non-hematological toxicities were generally mild or reversible.The recommended doses of this combination chemotherapy are 40mg/m²/day etoposide for 21 days and 350 mg/m² carboplatin onday 1. The response rate for non-small cell lung cancer andsmall cell lung cancer was 16.7% and 60% (95% confidence intervalsof 3.6% to 41.4%, and 14.7% to 94.7%), respectively. A phaseII study is necessary to define the efficacy and safety of thiscombination chemotherapy.     

A phase II trial of 5-fluorouracil and cisplatinum in recurrent or metastatic nasopharyngeal carcinoma

Background: A phase II clinical trial of the combination of5-fluorouracil (5-FU) and cisplatinum (CDDP) was conducted in24 patients (pts) with recurrent or metastatic nasopharyngealcarcinoma. None of the patients had prior chemotherapy and allbut 4 had prior radiotherapy. Patients and methods: 5-FU was administered by intravenous (i.v.)infusion at a dose of 1000 mg/m² daily on days 1 to 5 and i.v.infusion of CDDP at a dose of 100 mg/m2 in divided doses ondays 1 to 3 of each 21-day cycle. Pts were examined for responseafter every two cycles. Of 24 pts accrued, 21 had measurabledisease. Three had only bone metastases and were evaluable fortoxicity and survival. Results: Thirteen pts had partial response and three achievedcomplete response, for an overall response rate of 66% (95%confidence interval 59% to 93%). Median time to progressionfor all patients was 8 months (range 4 to 28+ months) and mediansurvival for all patients was 11 months. Grades 3 to 4 toxicitiesincluded granulocytopenia (10 pts). There was no treatment-relatedmortality. Average relative dose intensity was 0.8. Conclusion: This combination is highly effective with acceptabletoxicity. The duration of response tended to be brief. Its rolein the neoadjuvant and adjuvant setting in patients with poorprognostic features should be further studied. 5-fluorouracil, cisplatinurn, nasopharyngeal carcinoma     

Detection of O6-butyl- and O6-(4-hydroxybutyl)guanine in urothelial and hepatic DNA of rats given the bladder carcinogen N-nitrosobutyl(4-hydroxybutyl)amine

N-Nitrosobutyl(4-hydroxybutyl)amine (BBN) is a selective bladdercarcinogen in rats. Its organ specificity may depend on severalfactors, including metabolic activation, DNA alkylation andrepair within the target organ. Metabolic activation of BBN,which is asymmetrical, may result in butylating and 4-hydroxybutylatingspecies. To test this view, BBN was administered as a singleoral dose of 20 or 120 mg/rat or six doses of 20 mg/rat over2 weeks. The animals given the single 120 mg dose were killed3, 6 and 24 h after treatment Rats given 20 mg or 6x20 mg BBNwere killed 24 h after the last dose. DNA from liver and urothelialcells was hydrolyzed and analyzed for O⁶- butylguanine (O⁶-BuG)and O⁶-hydroxybutyOguanine [O⁶-(4-OH-Bu)G] as their pentafluorobenzyl-trimethylsilylderivatives by high-resolution gas chromatography—negativeion chemical ionization mass spectrometry with selective ionrecording after immunoaffinity extraction. Polyclonal antibodiesraised against O⁶-(4-hydroxybutyl)- guanosine [O⁶-(4-OH-Bu)GR]were coupled to CNBractivated Sepharose 4B. This was mixed witha gel coupled to antibodies raised against O⁶-BuG, already availablein the laboratory, and the mixed gel was used for the one-stepsample clean-up, enrichment and extraction of O⁶-(4-OH-Bu)Gand O⁶-BuG from hydrolyzed DNA. O⁶- BuG In urothelial DNA ofrats given a single dose of 120 mg BBN increased from 0.44 ±0.12 (µmol/mol guanine (mean ±SE) 3 h after treatment,to 17.9 ± 7.23 µmol/mol guanine at 24 h. O⁶-(4-OH-Bu)Gin the same tissue was 7.7 ± 3.19 (µmol/mol guanine3 h after treatment and 12.2 ± 7.01 µmol/mol guanineat 24 h. O⁶-BuG and O6-(4- OH-Bu)G were always lower in theliver than in urothelialcells. Twenty-four hours after a singledose of 20 mg BBN, urothelial O⁶-BuG was 5.41 ± 1.73(µmol/mol guanine anddid not accumulate after six dosesof 20 mg/rat BBN, since it was 2.59 ± 1.23 (µmol/molguanine 24 h after the last dose. O⁶-BuG in liver DNA was detectableafter the single dose of 20 mg, but not after 6x20 mg/rat BBN.O⁶-(4-OHBu) G was not detected in either the bladder or theliver after 20 mg or after the six doses of BBN. The resultsindicate that both butylating and 4-hydroxybutylating speciesare formed in the target organ DNA of rats given the bladdercarcinogen BBN, but that O⁶-BuG seems to be the lesion mostrelevant to the carcinogenic effect     

A Preliminary Report of Phase I and II Study of N4-Behenoyl-1-{beta}-D-arabinofuranosylcytosine (BH-AC) in Patients with Acute Leukemia and Other Malignancies

N⁴-Behenoy1-1-ß-D-arabinofuranosy1cytosine (BH-AC)was administered to 11 patients with acute leukemia and fivepatients with other malignancies in a Phase I and TI clinicaltrial. Among 16 patients, 14 received BH-AC after being refractoryto prior therapies, and two with acute leukemia received BH-ACfor their first remission induction therapy. The starting dose was 1.5mg/kg administered as a single i.v.infusion of three hours. The doses were then escalated up to5.0 mg/kg. No side effects were noted with single i.v. infusions.Daily consecutive infusions of 2.0 mg to 6.0 mg/kg for fourto 21 days resulted in two patients experiencing nausea, twoanorexia and one developing skin eruptions. Significant hematologicaleffects were noted by the daily infusions. One patient withacute myeloblastic leukemia achieved complete remission with5.0 mg/kg BH-AC administered daily for 21 days. BH-AC is active in acute leukemia and may play a role in thecombination regimens for this disease.     

Phase I Trial ofU racil-Tegafur (UFT) plus Oral Leucovorin: 28-Day Schedule

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m²/day, with planned escalations to 250, 300, 350, and 400 mg/m²/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m²/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m² level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m²/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and “hand-foot syndrome“ were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.     

Reversion of 6-thioguanine resistant Chinese hamster cell lines: agent specificity and evidence for the repair of promutagenic lesions

The kinetics and mutagen specificity of reversion of an HGPRT-TG^Rline of Chinese hamster cells have been examined in detail bymeasuring the frequency of HAT^R colonies. Alkylating agentswhich produce relatively high levels of O-atom reaction wereeffective in inducing reversion. MMS, DMS and u.v. were lessefficient, and aflatoxin B₁, acridine orange and N-acetoxy-AAFwere completely ineffective. For agents which were effective,the relationship between HAT^R colony frequency and dose of mutagenwas linear at early expression times (6 h). HAT^R colony frequencyfell subsequently at all doses and the rate and extent of thefall was inversely related to dose. These observations suggestrepair of a pro-mutagenic DNA lesion. Other TG^R mutants isolatedfrom the same wild-type cell line under different selectiveconditions were also tested for revertibility after exposureto the same mutagens. The majority did not revert, this suggeststhat they carry deletions within the structural gene for HGPRT.The infrequent revertible lines all arose spontaneously andour evidence suggests that they carry nonsense mutations.     

A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci

The relative response to various initiating doses of diethylnitrosamine(DEN) and dimethylbenz[a]anthracene of the induction of numbersand size (vol. % of liver) of altered hepatic foci (AHF) inlivers of adult female rats of the Sprague-Dawley and Fischer344 (F-344) strains was studied by methods of quantitative stereologyin the presence and absence of the promoting agent, phenobarbital(PB, 0.05% in the diet). In all cases, a relatively linear responsewith dose, even at the lowest doses employed, was obtained exceptfor the numbers of AHF at the highest dose of DEN (30 mg/kg),which was not significantly different from that at a dose of10 mg/kg in F-344 female rats. Similar dose-response data wereobtained at various doses of two promoting agents effectivein hepatocarcinogenesis, PB and 2,3,7,8-tetrachloro-dibenzo-p-dioxin(TCDD), in livers of F-344 female rats following initiationwith DEN (10 mg/kg) 24 h post-70% hepatectomy. The responseto these agents exhibited threshold levels below which no increasein number or vol. % of liver of AHF was noted in comparisonwith that in livers of animals not treated with the promotingagents. At several subthreshold doses of both PB and TCDD aninhibition of AHF formation and growth (measured as vol. % ofliver) was observed. Based on quantitative stereologic calculations,parameters for the estimation for the relative potency of chemicalsas initiating or promoting agents have been established. Theseare defined as: initiation index = no. of foci induced x liver^–1x [mmol/kg body wt]^–1 and promotion index = V_f/V_c x mmol^–1x weeks^–1 where V_f is the total volume fraction (%) occupiedby AHF in the livers of rats treated with the test agent andV_c is the total volume of AHF in control animals which haveonly been initiated. These parameters were calculated for anumber of agents based on data published in the literature andfrom those reported herein. Neither parameter varied significantlywith the dose of the initiating agent based on the data in thispaper. The range of promotion indices extended over more thaneight orders of magnitude, whereas that of initiation indiceswas much less variable. Such parameters may be useful as quantitativeestimates of the potency of hepatocarcinogenic agents, suchvalues having potential application to risk estimations.     

Gemcitabine is an active new agent in previously untreated extensive small cell lung cancer (SCLC): A study of the National Cancer Institute of Canada Clinical Trials Group

BACKGROUND: The new pyrimidine antimetabolite Gemcitabine has shown preclinicalefficacy in a number of solid tumour lines and acceptable toxicityin phase I trials. As part of an ongoing effort to identifyactive new agents in small cell lung cancer, the NCIC ClinicalTrials Group studied Gemcitabine in previously untreated patientswith extensive disease. PATIENTS AND METHODS: Twenty-nine newly diagnosed patients with untreated extensivesmall cell lung cancer and at least one bidimensionally measurablesite received Gemcitabine as a 30 minute intravenous infusionweekly x 3 every 4 weeks. The starting dose was 1000 mg/m²/weekin the first 17 patients and 1250 mg/m²/week in the remainder.Patients were reevaluated for response every 4 weeks. Thosefailing to respond after 2 cycles of therapy were to be offeredstandard chemotherapy. RESULTS: Of the 29 patients entered, all were evaluable for toxicityand 26 for response. One complete and 6 partial responses wereseen giving a response rate of 27% (95% CI: ll%–47%).Median response duration was 12.5 weeks and the median survivalof the entire population was 12 months. Toxic effects were mildto moderate: in particular serious myelosuppression was uncommon. CONCLUSIONS: Gemcitabine is active in previously untreated small cell lungcancer in doses which produce little toxicity. Combination studiesof Gemcitabine with other agents active in this disease arewarranted. gemcitabine, phase II trial, small cell lung cancer     

An EORTC pilot study of filgrastim (recombinant human granulocyte colony stimulating factor) as support to a high dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer

BACKGROUND: In an attempt to increase chemotherapy dose intensity by step-wisereduction of the time interval between treatment cycles, filgrastimwas administered to breast cancer patients receiving a three-monthcombination chemotherapy with epirubicin (E) and cyclophosphamide(C). PATIENTS AND METHODS: Chemotherapy-naïve patients with locally advanced or metastaticbreast cancer received fixed doses of E (120 mg/m²) and C (830mg/m²) by 15-min i.v. infusion on day 1 of each cycle and filgrastimat a dose of 4 µ/kg once daily by SC injection starting24 hours after chemotherapy. Cohorts of patients were treatedin successive schedules, each schedule corresponding to a specifiedtime interval between chemotherapy cycles. The toxicity observedin each schedule was evaluated before patients were accruedto the next schedule, which corresponded to a shorter time intervalbetween chemotherapy cycles. RESULTS: The maximum tolerated schedule was E (120 mg/m²) plus C (830mg/m²) given every 14 days with filgrastim support from day2 until day 13. On this schedule, 5 of 12 patients experienceddose-intensity-limiting toxicities (DLT) during the 3-monthstudy period. Non-hematological DLT occurred in 2/12 patients(mucositis, skin toxicity) while 3/12 experienced febrile neutropeniarequiring i.v. antibiotics. All patients achieved recovery ofANC to > 1.5 x 10⁹/l by the time of scheduled retreatment.The combination of filgrastim with this regimen did not seemto add major toxicities. The efficacy was high, with 87% ofpatients achieving an objective response and a median responseduration of 18 months (range: 4–;52 months). CONCLUSIONS: Filgrastim permits at 33% increase in ‘EC’ doseintensification over that of the conventional every-3-week administration.Randomized studies should now be initiated to evaluate the merit,if any, of ‘accelerated’ chemotherapy in advancedbreast cancer. chemotherapy dose-intensification, breast cancer, hematopoietic growth factor     

Lack of induction of O6-methylguanine-DNA methyltransferase in mammalian cells treated with N-methyl-N''-nitro-N-nitrosoguanidine

A synthetic DNA substrate containing O⁶-methyI(8-³H)guaninewas used to assay demethylation of the premutagenic base byO⁶-methylguanine-DNA methyltransferase in extracts of HeLa cells,Chinese hamster ovary cells and normal rat kidney cells whichhad been treated with multiple doses of N-methyl-N' -nitro-N-nitrosoguanidine(MNNG). No induction of methyltransferase activity was observedin any of the cell lines tested. Constitutive levels of methyltransferasein cell lines proficient (Mex⁺) in O⁶-methylguanine repair weredecreased in a dose-dependent fashion by either single or multipletreatments with MNNG over a broad range of dose levels. Recoveryof constitutive levels of activity required 24-to 48-h incubationperiods. Repair deficient (Mex^–) cell lines lacked bothconstitutive and inducible methyltransferase activity.     

High-dose radiotherapy plus prolonged hormone therapy in CT2-3 prostatic carcinoma: is it useful?

AIMS AND BACKGROUND: Clinical studies published in the last decade have shown the possible improvement in prognosis of patients with prostatic carcinoma undergoing radiation therapy with dose escalation or in combination with hormone therapy. However, in studies on hormone therapy, moderate doses of radiation therapy have been used, whereas in studies with high-dose radiotherapy, hormone therapy usually was not administered. Therefore, it is not clear whether the concomitant use of high doses and prolonged hormone therapy could determine an additional beneficial effect. The aim of the present study was therefore to evaluate the relative prognostic role of different dose levels (< 70 versus > or = 70 Gy) of external beam radiotherapy and of different hormone therapies (neoadjuvant only versus neoadjuvant + adjuvant). METHODS: A total of 426 patients (median age, 71 yrs; range, 51-87 yrs) underwent external beam radiotherapy (70 Gy median dose to prostate volume +/- 45 Gy to pelvic lymph nodes) and neoadjuvant hormone therapy (bicalutamide for 30 days; goserelin, 3.6 mg every 28 days starting two months before radiotherapy and for its entire duration). Dose to the prostate was < 70 Gy in 44.8% of patients and > or = 70 Gy in 55.2%. A total of 244 patients received adjuvant hormonal therapy. The distribution according to the clinical stage was 48.1% T2 and 51.9% T3. The distribution according to the Gleason score was 14.3% grades 2-4, 66.7% grades 5-7 and 19.0% grades 8-10. The distribution according to pretreatment prostate-specific antigen levels (in ng/mL) was 7.0% for 0-4, 29.3% for 4-10, 30.3% for 10-20, and 33.3% for > 20. RESULTS: With a median follow-up of 35 months (range, 1-151), 81 patients (19.0%) showed biochemical recurrence, 17 patients (4.0%) showed local disease progression, and 12 patients (2.8%) showed distant metastases. Overall, 23 patients (5.4%) showed disease progression. Four patients (0.9%) died. At the time of this writing, no patient has died from prostatic carcinoma. At univariate analysis, the radiation dose delivered to the tumor and the administration of adjuvant hormone therapy were shown to be significantly correlated with biochemical disease-free survival. At multivariate analysis, the single parameter significantly correlated with biochemical disease-free survival was the radiation dose delivered to the tumor. In the subset of patients not treated with adjuvant hormone therapy, there was a significant correlation between radiation dose and biochemical disease-free survival at univariate and multivariate analysis. A similar correlation between adjuvant hormone therapy and biochemical disease-free survival was observed in the subset of stage cT3 patients at univariate and multivariate analysis. In patients undergoing combined treatment without adjuvant hormone therapy, a significant correlation was observed between clinical stage and biochemical disease-free survival, at univariate and at multivariate analysis. CONCLUSIONS: The results of the study confirmed the positive impact of radiotherapy doses > 70 Gy and of adjuvant hormone therapy in patients with locally advanced prostatic carcinoma. Owing to the lack of evidence of a correlation between radiation dose and biochemical outcome in patients undergoing prolonged hormone therapy, the role of further dose escalation in patients undergoing combined hormone and radiation therapy is still unclear.     

Primary therapy of multiple myeloma with paclitaxel (Taxol)

BACKGROUND: The treatment of multiple myeloma remains unsatisfactory andnew active agents are needed. Paclitaxel is effective againsta variety of solid tumors and we assessed the utility againstmultiple myeloma. PATIENTS AND METHODS: From March 1993 to May 1994, we treated 33 patients with newlydiagnosed multiple myeloma with paclitaxel given intravenouslyat a dose of 125 mg/m² over 24 hours (13 patients) or at a doseof 135 mg/m² over 3 hours (20 patients). RESULTS: Five of 33 patients responded (15%; 95% CI: 5 to 32%) with anunmaintained remission of 3–11+ months. Severe but reversibleneutropenia was the major dose limiting toxicity, but myalgiasand alopecia were also common. CONCLUSIONS: Paclitaxel was slightly active against multiple myeloma. Whetherhigher doses or new analogues of this agent can produce superiorresults requires further study. multiple myeloma, paclitaxel