<Emphasis Type="BoldItalic">ATM</Emphasis> Polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) ageof onset (United States)

Objective: We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families.Materials and methods: We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis.Results: The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population.Conclusions: Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.*This grant was supported by Grant CA70759 from the National Cancer Institute, by NIH Cancer Center Support Grant CA16672 and also, by a cancer prevention fellowship from the National Cancer Institute, Grant R25 CA57730.     

Cumulative renal tubular damage associated with cisplatin nephrotoxicity

Summary We assessed the acute and chronic effect of multiple courses of cisplatin therapy on renal tubules by monitoring the urinary excretion of alanine aminopeptidase, N-acetyl--D-glucosaminidase, and total protein. Urine specimens were obtained before and after doses of cisplatin (90 mg/m²) given to 12 patients. Each dose of cisplatin induced transient increases in enzyme excretion, followed by proteinuria 3–5 days later. Transient enzymuria after the last cisplatin dose was significantly greater than that after the first dose. Moreover, persistent increases in urinary N-acetyl--D-glucosaminidase and serum creatinine concentrations over pretherapy levels indicated chronic renal tubular damage. Our findings disclosed striking differences between patients in susceptibility to progressive nephrotoxicity.Supported by Biomedical Research Support Grant RR05584 (MPG), Cancer Center Support Grant (CORE) CA-21765, Chilhood Solid Tumor Program Project Grant CA-23099 and the American Lebanese Syrian Associated Charities (ALSAC)     

The effects of cimetidine upon the plasma pharmacokinetics of doxorubicin in rabbits

Summary Cimetidine is an H₂ antagonist which inhibits cytochrome P-450 and reduces hepatic blood flow. To determine whether cimetidine interferes with the plasma pharmacokinetics of doxorubicin, we gave six female New Zealand rabbits doxorubicin 3 mg/kg, followed a month later by cimetidine 120 mg/kg every 12 h over 72 h and doxorubicin 3 mg/kg. Serial plasma specimens were obtained over 72 h and assayed for doxorubicin and its metabolites by high-performance liquid chromatography and fluorescence detection.Doxorubicin plasma pharmacokinetics were prolonged after cimetidine pretreatment [AUC 0.76±0.22 vs. 2.85±1.22 M×h, no pretreatment vs pretreatment (p=0.005), half-life=11.7±6.55 vs 28.0±8.16 h (P=0.0002), and clearance=0.129±0.036 vs 0.036±0.0111/min^-1 kg^-1 (P=0.0007)]. No significant differences were found between the AUCs for doxorubicinol, 7-deoxy doxorubicinol aglycone, or two unidentified nonpolar metabolites in nonpretreatment and pretreatment studies. Cimetidine increases and prolongs the plasma exposure to doxorubicin in rabbits. Doxorubicin metabolism does not appear to be affected by cimetidine.Grant Support Veterans Administration, NIH Grant RR-05424 and Clinical Research Center Grant RR-00095 American Cancer Society Institutional Grants #IN25V and IN24V, and JFCF #649     

Expressions of resistance and cross-resistance in teniposide-resistant L1210 cells

Summary Resistance to teniposide (VM-26) by VM-26 selected resistant L1210 cells in culture was attributed to alterations in the flux of VM-26 across the plasma membrane and to functions of homogeneously staining regions that appeared on one or more chromosomes. In the present study, electrophoresis of membrane-cytosol fractions of these resistant sublines demonstrated a protein band, M_r 22 kd, that was not evident in similar fractions of drugsensitive L1210 cells or three revertant sublines. The distribution of this protein among various cellular fractions could be altered by manipulation of the concentration of calcium ions. A representative subline, LIa5 M, was observed to have vesicles that reacted with Sudan black B stain, an indication of altered lipid metabolism. The LIa5 M subline was cross-resistant to etoposide, vincristine, doxorubicin, amsacrine, and actinomycin D. Concentrations of VM-26 that inhibited cell division to the same extent caused an accumulation of fewer cells in the G₂ stage of cell division in LIa5 M cultures than in L1210 cultures. These observations indicate that the LIa5 M subline expressed multiple drug resistance, as well as changes in the expression of cytotoxicity to VM-26.This investigation was supported by Research Project Grant CA 35319, by Cancer Center Support (CORE) Grant CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.Recipient of research support from a training grant, American Cancer Society Grant IN-85-06, to the University of Tennessee Center for the Health Sciences     

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin in rabbits

Summary The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a ¹⁴C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone =1.44±0.88 M·h/ml vs 4.49±2.35 M·hr/ml for doxorubicin given with high-dose ranitidine; P=0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. ¹⁴C-Aminopyrine half-life was altered by a raniditine dose of 25 mg/kg (aminopyrine half-life after placebo control =97±6 min as against aminopyrine half-life after ranitidine =121±7 min; mean±SEM; P<0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.Grant support: Glaxo Inc., Veterans Administration, NIH BRSG RR-05424, NIH Grant RR-00095, Clinical Research Center. American Cancer Society Institutional Grant IN25V     

Intraperitoneal 5-fluoro-2′-deoxyuridine (FUDR) and (S)-leucovorin for disease predominantly confined to the peritoneal cavity: a pharmacokinetic and toxicity study

Intraperitoneal (IP) administration of fluorinated pyrimidines has been evaluated for ovarian and gastrointestinal malignancies in phase I, II, and III trials. The tolerance and pharmacokinetic profile of IP 5-fluoro-2-deoxyuridine (FUDR) alone and with (R,S)-leucovorin ((R,S)-LV) have each been evaluated in previous phase I studies. FUDR doses of 3 g per day with and without (R,S)-LV doses up to 640 mg per day given IP are well tolerated. The current phase I study was designed to determine the pharmacokinetic profiles and clinical tolerance of escalating doses of the pure biologically activeS-isomer of leucovorin ((S)-LV) given IP with the same dosing schedule of FUDR. A group of 16 patients with disease confined to the abdominal cavity were treated in this study. Pharmacokinetic studies of blood and peritoneal fluid, toxicity profiles, and clinical response for the first three cycles are reported here. The toxicity profile did not significantly differ from the prior two studies. All nonhematologic toxicities, such as fatigue, nausea, vomiting, diarrhea, and abdominal discomfort were less than grade 4, and most were less than grade 3. Neutropenia and thrombocytopenia were uncommon and observed only in patients with compromised bone marrow reserve. The pharmacokinetic profiles were also congruent with the previous studies and indicate a three-log advantage for FUDR. The (S)-LV profiles in the peritoneal cavity paralleled those of FUDR. Antitumor effects or absence of progression until after cessation of therapy were documented in 11 patients. At a median follow-up of 18 months 44% of patients were alive. IP administration of 3-g of FUDR and up to 640 mg (S)-LV daily for three days was well tolerated. The tolerance and antitumor effects observed during IP FUDR and LV in these studies encourage further exploration of this regimen against ovarian and gastrointestinal malignancies. The actual role and optimal dose of LV as an enhancer of the antitumor actions of FUDR administered by this route remain unknown.Supported in part by RO1 CA-50412, Cancer Center Core Grant, and NIH National Center for Research Resources of the General Clinical Research Center Grant MO1RR-43     

Effects of DFMO-induced polyamine depletion on human tumor cell sensitivity to antineoplastic DNA-crosslinking drugs

Summary We investigated the effect of pretreatment with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, on the cytocidal responses of four human adenocarcinoma cell lines to two alkylating and crosslinking agents: chlorambucil and N,N,N-triethylenethio-phosphoramide (thiotepa). The cell lines studied included HuTu-80 (duodenum), HT-29 (colon), ME-180 (cervix), and A-427 (lung). A 48- to 72-h pretreatment with DFMO reduced intracellular putrescine and spermidine contents to <10% and <1% of control levels. This treatment also caused a 30%–70% decline in spermine content. Survival of control and DFMO-pretreated cells after treatment with chlorambucil or thiotepa was measured by a plating efficiency assy. For three of the four lines studied, the DFMO-induced partial polyamine depletion significantly protected cells from the lethal effects of chlorambucil. In ME-180 cultures alone, DFMO pretreatment did not alter the cytocidal efficacy of chlorambucil. Addition of exogenous putrescine to cultures of HuTu-80, HT-29, or A-427 24 h after DFMO addition but 24 h before treatment with chlorambucil reversed the polyamine depletion and its protective effects on chlorambucil-induced cell kill. In contrast to the above observations, DFMO and partial polyamine depletion had no effect on cell survival after thiotepa treatment for any of the cell lines investigated.Abbreviations BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea - CENU chloroethylnitrosourea - cis-Pt (II) cis-diamminedichloroplatinum (II) - DFMO difluoromethylornithine - ODC ornithine decarboxylase - PU putrescine - SD spermidine - SP spermine thiotepa - N,N,N triethylenethiophosphoramide This investigation was supported in part by PHS grant no. CA-32758 awarded by the National Cancer Institute, DHHS; by grant no. 82-6 from the American Cancer Society, Ill. Div., Inc.; and by a Biomedical Research Support Grant to Northwestern University Medical School from the US PHS, NIH (RR-05370)     

Phase II trial of VP16-213 in non-small cell lung cancer (NSCLC)

Summary Fifty-one patients with non-small cell lung cancer (NSCLC) were treated, during a phase II trial, with 4 demethylepipodophyllotoxin--d-ethylidene glucoside (VP16-213). Forty-nine were evaluable for response, and of these two (4%) had partial responses lasting 5 and 6 months. Prior treatment with chemotherapy may have adversely affected response rate; none of the 24 previously treated patients had a major response. Myelosuppression was the dose limiting toxicity. Anorexia, nausea and vomiting, partial alopecia, and chills plus hypotension during drug infusion were the other toxic effects. We conclude that VP16-213 has only minimal activity as a single agent in NSCLC.Supported in part by NIH Grant No. CA-05826 and CA-09027, and by NCI Contract NO-1-CM 972744Demethylepipodophyllotoxin--d-Ethylidene Glucoside (NSC141540) was supplied by the Drug Evaluation Branch of the National Cancer Institute     

No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers

Purpose

Lenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated.

Methods

Two phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300–600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs.

Results

There were no significant changes in the maximum concentration (C _max) and area under the plasma concentration–time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C _max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C _max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed.

Conclusions

There are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.     

The importance of schedule on diethyldithiocarbamate modulation of drug-induced myelosuppression

Summary Sodium diethyldithiocarbamate (DDTC) has been investigated as a biochemical modulator of the toxicity associated with clinically used cancer chemotherapeutic agents. In the present study, we assessed the ability of DDTC to accelerate recovery of the granulocyte/macrophage progenitor cel (GM-CFC) population following treatment with the myelosuppressive drugs carboplatin (CBDCA), tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum(IV) (tetraplatin), 5-fluorouracil (5-FU), and etoposide (VP-16) in B6D2F₁ mice. Myelotoxicity was assessed 24 h after the injection of the anticancer drug using a GM-CFC clonogenic assay. In the case of all four anticancer drugs, the timing of DDTC administration appeared to be a critical parameter with regard to protection. A delay time of 1 h between the injection of the myelotoxic drug and treatment with DDTC (30 mg/kg) resulted in a significant reduction in cytotoxicity to GM-CFC, whereas a longer delay time did not. These results suggest that the timing of DDTC administration may be essential in modulating the myelosuppression associated with many chemotherapeutic regimens used in the clinic.Abbreviations DDTC sodium diethyldithiocarbamate - cDDP cis-diamminedichloroplatinum - CBDCA diammine(1,1-cyclobutanedicarboxylato)platinum(II) - tetraplatin tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum(IV) - GM-CFC granulocyte/macrophage colony-froming unit - -MEM -minimum essential medium - PWM-SCCM pokeweed mitogen-stimulated spleen-cell conditioned medium This work was supported by grants CA 34 260 and CA 11 098 from the National Cancer Institute, NIH, DHHS     

Reversible inhibition of human thioredoxin reductase activity by cytotoxic alkyl 2-imidazolyl disulfide analogues

The thioredoxin/thioredoxin reductase system is important for several aspects of the regulation of cellular proliferation by both intracellular and extracellular mechanisms. The effects ofn-butyl 2-imidazolyl disulfide (III-2), 1-methylpropyl 2-imidazolyl disulfide (IV-2), andn-decyl 2-imidazolyl disulfide (VII-2) on purified human placental thioredoxin reductase activity were examined. The analogues were competitive inhibitors with DTNB for reduction by thioredoxin reductase, withK _i values for III-2, IV-2, and VII-2 being 3.3, 13.0, and 8.6 M, respectively. The inhibition was noncompetitive with reduced nicotinamide adenine dinucleotide phosphate (NADPH). None of the analogues was a suicide substrate inhibitor of the flavoenzyme. III-2 and VII-2 were metabolized by thioredoxin reductase at about half the rate of DTNB, whereas IV-2 was not detectably metabolized. The second order rate constants for the reactions of III-2 and IV-2 with reduced GSH were 931 and 91M ^–1 s^–1, respectively. The lower reactivity of IV-2 with reduced GSH and the lack of the analogue's metabolism by thioredoxin reductase may be due to the more sterically hindered structure of this analogue. The 50% inhibitory concentrations (IC₅₀ values) for the inhibition of serum-dependent cellular proliferation of Swiss 3T3 murine fibroblasts by III-2, IV-2, and VII-2 were 2.0, 3.5, and 4.0 M, respectively. IV-2 was considerably more potent as an inhibitor of the thioredoxin-dependent cellular proliferation of Swiss 3T3 fibroblasts, showing an IC₅₀ value of 60 nM. Thus, inhibition of cellular proliferation by alkyl 2-imidazolyl disulfide analogues may involve interaction with thioredoxin, thioredoxin reductase, or an alternative target that is redox-regulated by thioredoxin.Abbreviations DMEM Dulbecco's modified Eagle's medium - DTNB 5,5-dithiobis-(2-nitrobenzoic acid) - DTT dithiothreitol - FBS fetal bovine serum - GSH glutathione - Trx thioredoxin - TR thioredoxin reductase This work was supported by NIH grant CA 42286 (G.P.), NIH Training Grant in Cancer Biology CA 09213 (J.E.O.), and MRC Canada MA-10163 (D.L.K.)     

Correlations between experimental chemotherapy in the murine glioma and effectiveness of clinical therapy regimens

Summary Intracerebral murine glioma 26 was used as a model system for evaluating two-drug combinations of antitumor agents. BCNU was combined with either procarbazine, dianhydrogalactitol, or ellipticine. CCNU was combined with procarbazine. All combinations were more active than the individual drugs alone. The most potent combinations achieved 85–100% tumor cure at 120 days, with combined toxicity indices of 0.25 (CCNU-procarbazine) to 1.30 (BCNU-dianhydrogalactitol). The experimental data were compared to clinical studies with CCNU, procarbazine, and vincristine, and BCNU-procarbazine.American Cancer Society Faculty Research Award FRA-155This work was supported by NIH Center Grant CA-13525, and gifts from Phi Beta Psi Sorority and the Margaret M. Anton Memorial Fund Reprint requests should be addressed to:Editorial Office, 350 Parnassus Avenue, Suite 807, University of California, San Francisco, California, 94143, USA     

Gender of the first offspring,age at diagnosis,and survival with breast cancer (Utah,United States)

We examined the relationship between the survival of women with breast cancer and the gender of their first children using a genealogy-based survival analysis. The study group consisted of 2,155 parous women diagnosed in Utah (United States) with first primary breast cancers (excludingin situ tumors). We calculated hazard rate ratios (HRR) which were adjusted for stage, median survival times, and proportions surviving for three-, five-, and 10-year intervals stratified by age at diagnosis. Median survival among women diagnosed under the age of 45 was 171 months if the first child was female, but only 66 months if the first child was male (HRR=1.66, 95 percent confidence interval=1.07–2.57, for male children). For women diagnosed at age 45 or older, all survival times were similar, although women whose first child was male had slightly longer median survival time. These findings suggest that the gender of the first child has a strong influence on survival among women diagnosed under 45 years of age, but not among those diagnosed later in life. Gender of the first offspring may be a useful clinical indicator of prognosis and survival and may provide insights into etiologic and promotional factors for breast cancer.Cancer Causes and Control 1994, 5, 26–30.Support for this research was, in part, from NIH Grant P30 CA42014, US National Cancer Institute, National Institutes of Health and the Utah Cancer Registry, National Cancer Institute contract NO1-CN0522.     

A case-control study of risk factor for renal cell cancer in northern Italy

A hospital-based case-control study of renal cell cancer was conducted in northern Italy betwen 1986 and 1989, with 240 cases of renal cell cancer (150 males and 90 females), and 665 controls (445 males and 220 females) chosen on the basis of age, sex, and area of residence. No associations were found between renal cell cancer and: body mass index (BMI); number of cigarettes smoked; age at starting to smoke; years of smoking; consumption of wine, beer, spirits, coffee, decaffeinated coffee; tea; intake of animal protein, fruits, and vegetables; various resproductive factors; hormonal use; sexual habits; sexually transmitted diseases; or selected occupational exposures. The odds ratio (OR) was above unity in smokers (OR=1.34 for 15 cigarettes/day), but the trends in risk with dose or duration were not statistically significant. Significant positive associations were found between renal cell cancer and sources of fat intake, especially margarine (OR for highest vs lowest intake = 1.71), and oils (OR=1.89) whereas carrot intake showed a negative association (OR=0.62). Also, a history of nephrolithiasis and multiple episodes of cystitis showed weak positive associations (OR=2.00, 95 percent confidence interval (CI) 1.07–3.73; and OR=1.60, 95 percent CI 0.95–2.70, respectively).Address reprint requests to Dr Talamini. The work was conducted with the contribution of the Italian Association for Cancer Research, Milan, Italy and the CNR (Italian National Research Council) Applied Projects Oncology (Contract n. 85.02209.44).Drs Talamini, Barón, Barra, Bidoli, Serraino, and Franceschi are in the Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ. 33081 Aviano (PN) Italy. At the time of this work, Dr Barón was a visiting biostatistician from the Department of Preventive Medicine and Biometrics, University of Colorado, Health Science Center, CO, funded by the National Cancer Institute (US) and the Italian National Research Council. Dr Franceschi is also chief of the Hormones and Sexual Factors and Cancer Working Group of the European Organization for Cooperation in Cancer Prevention Studies, Bruxelles, Belgium. Drs La Vecchia and Negri are in the Mario Negri Institute for Pharmacological Research, Milan, Italy. Dr La Vecchia is also in the Institute of Social and preventive Medicine, University of Lausanne, Switzerland.     

Serum tamoxifen concentrations in the athymic nude mouse after three methods of administration

Summary The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. We hav examined the steady-state serum tamoxifen concentrations achieved in mice with s. c. slow-release pellets, s. c. injections, and i. p. injections, in an attempt to identify a method that would yield serum levels similar to those observed in patients receiving tamoxifen therapy. Tamoxifen and tamoxifen metabolites were examined by a high-performance liquid chromatography assay which has a sensitivity of 8 ng/ml. Tamoxifen metabolites were not observed with any dose or schedule. After slow-release pellets containing 5 or 25 mg tamoxifen no tamoxifen was detectable, even after 2 weeks of treatment. Very low levels (0.07 M) were found with 50-mg pellets. Tamoxifen was also not detected either with daily s. c. injections of 500 g/mouse or with i. p. injections of 2.5 mg/kg. However, daily s. c. injections of 1000 g or i. p. injections of 25, 50, o4 100 mg/kg resulted in tamoxifen concentrations ranging from 0.21 to 0.51 M which are similar to those observed in patients. Thus, clinically relevant tamoxifen concentrations can be achieved in the nude mouse with either of these methods of administration.This work was supported in part by NIH Grant CA 30251 from the National Cancer Institute and the Louis R. Lurie Foundation     

Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein

Summary We evaluated the multidrug resistance (MDR)-modulating effects of progesterone (PRG) and an orally active, structurally related compound, megestrol acetate (MA), in several MDR human cell lines. At 100 m, both steroids inhibited the binding of aVinca alkaloid photoaffinity analog to P-glycoprotein (P-gp) in MDR human neuroblastic SH-SY5Y/VCR cells [which show >1500-fold resistance to vincristine (VCR) in the tetrazolium dye (MTT) assay]. However, 100 m MA markedly enhanced the binding of [³H]-azidopine to P-gp in both SH-SY5Y/VCR cells and the MDR human epidermoid KB-GSV2 cell line (which displays 250-fold resistance to VCR in the MTT assay). PRG had little effect on the binding of [³H]-azidopine to P-gp. MA at low doses was more effective than PRG in sensitizing cells to VCR and enhancing their accumulation of [³H]-VCR. The highly resistant SH-SY5Y/VCR subline exhibited significant collateral sensitivity to both steroids. These data suggest that MA may be a clinically useful modulator of MDR.This work was supported by NIH grant CA-47652. The first author (G. E. F.) was supported by PHS grant DK07134-15     

Systematic review of current prognostication systems for primary gastrointestinal stromal tumors

Background

The advent of tyrosine kinase inhibitors as adjuvant therapy has revolutionized the management of GIST and emphasized the need for accurate prognostication systems. Numerous prognostication systems have been proposed for GIST but at present it remains unknown which system is superior. The present systematic review aims to summarize current prognostication systems for primary treatment-naive GIST.

Smoking and risk of breast cancer in carriers of mutations in <Emphasis Type="Italic">BRCA1</Emphasis> or <Emphasis Type="Italic">BRCA2</Emphasis> aged less than 50 years

Background Cigarette smoke contains compounds that may damage DNA, and the repair of damage may be impaired in women with germline mutations in BRCA1 or BRCA2. However, the effect of cigarette smoking on breast cancer risk in mutation carriers is the subject of conflicting reports. We have examined the relation between smoking and breast cancer risk in non-Hispanic white women under the age of 50 years who carry a deleterious mutation in BRCA1 or BRCA2. Methods We conducted a case-control study using data from carriers of mutations in BRCA1 (195 cases and 302 controls) and BRCA2 (128 cases and 179 controls). Personal information, including smoking history, was collected using a common structured questionnaire by eight recruitment sites in four countries. Odds-ratios (OR) for breast cancer risk according to smoking were adjusted for age, family history, parity, alcohol use, and recruitment site. Results Compared to non-smokers, the OR for risk of breast cancer for women with five or more pack-years of smoking was 2.3 (95% confidence interval 1.6–3.5) for BRCA1 carriers and 2.6 (1.8–3.9) for BRCA2 carriers. Risk increased 7% per pack-year (p < 0.001) in both groups. Conclusions These results indicate that smoking is associated with increased risk of breast cancer before age 50 years in BRCA1 and BRCA2 mutation carriers. If confirmed, they provide a practical way for carriers to reduce their risks. Previous studies in prevalent mutation carriers have not shown smoking to increase risk of breast cancer, but are subject to bias, because smoking decreases survival after breast cancer. Northern California Family Registry for Breast Cancer: AS Whittemore, Stanford University School of Medicine, EM John, Northern California Cancer Center, A Felberg, Stanford University School of Medicine, V McGuire, Stanford University School of Medicine, DW West, Northern California Cancer Center, A Miron, Dana-Farber Cancer Institute, Harvard Medical School, DC Thomas, USC Keck School of Medicine, R Haile, USC Keck School of Medicine and Norris Comprehensive Cancer. Fox Chase Familial Breast Cancer Registry: M Daly, Fox Chase Cancer Center, A Godwin, Fox Chase Cancer Center, E Ross, Fox Chase Cancer Center. Coriell Institute: J Beck. New York Familial Breast Cancer Registry: MB Terry, Joseph L. Mailman School of Public Health, Columbia University. Utah Breast Cancer Family Registry: SS Buys, Huntsman Cancer Institute, V Venne, Huntsman Cancer Institute. Australian Breast Cancer Family Study: JL Hopper, The University of Melbourne, GG Giles, The Cancer Council Victoria, MRE McCredie, University of Otago, New Zealand, RL Milne, Spanish National Cancer Centre, MC Southey, The University of Melbourne, MA Jenkins, The University of Melbourne, C Apicella, The University of Melbourne. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre. Ontario Familial Breast Cancer Registry: I Andrulis, Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, NF Boyd, Ontario Cancer Institute, J Knight, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, H Ozcelik, Samuel Lunenfeld Research Institute, Mount Sinai Hospital. Correspondence to: Dr NF Boyd, Campbell Family Institute for Breast Cancer Research, Room 10-415, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario, Canada M5G 2M9. Boyd@uhnres.utoronto.ca     

The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug–drug interactions

Purpose

Lenalidomide is an immunomodulatory agent used for the treatment of myelodysplastic syndromes and multiple myeloma. Renal clearance of lenalidomide is the predominant elimination route and is approximately twofold greater than the glomerular filtration rate (GFR), suggesting the potential contribution of an active secretory mechanism. In vitro studies were conducted to examine whether lenalidomide is a substrate of drug transporters, namely P-glycoprotein (P-gp), human breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP1, MRP2, MRP3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1 and OCT2), human organic cation transporter novel 1 and 2 (OCTN1 and OCTN2), multidrug and toxin extrusion (MATE1) and organic anion transporting polypeptide (OATP1B1). Lenalidomide was also evaluated as an inhibitor of P-gp, BCRP, MRP2, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 and bile salt export pump (BSEP). In addition, inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1) variants by lenalidomide was also assessed.

Method

Cells or vesicles expressing each of the human transporters were used for uptake and inhibition studies, with appropriate probe substrates and known inhibitors.

Results

Results of these studies indicate that the lenalidomide is not a substrate for the transporters examined, except that it is weak substrate of P-gp. None of the transporters studied were inhibited by lenalidomide. Lenalidomide is not an inhibitor of UGT1A1*1/*1 or its polymorphic variants UGT1A1*1/*28 and UGT1A1*28/*28.

Conclusions

Drug interactions are unlikely to occur when lenalidomide is co-administered with substrates or inhibitors of these transporters. In addition, lenalidomide is unlikely to cause interactions when co-administered with substrates of UGT1A1.     

Association of Vasectomy and Prostate Cancer Among Men in a Maryland Cohort

Objectives To evaluate the association of vasectomy with prostate cancer. Methods Participants were male members of the CLUE II cohort followed since 1989. On a questionnaire mailed in 1996, the men were asked if they had had a vasectomy and their age at vasectomy. Between 1996 and April 2004, 78 prostate cancer cases were confirmed among the 3373 men who were at least 35 years old at baseline and who completed the questions about vasectomy. Cox proportional hazards regression was used to estimate age-adjusted hazard ratios (HR) of prostate cancer. Results The HR for prostate cancer for men who had had a vasectomy was 2.03 (95% CI: 1.24–3.32). Risk of low-grade disease (HR=2.87; 95% CI 1.49–5.54), but not high-grade disease (HR=0.99; 95% CI 0.36–2.76), was higher in men who had had a vasectomy. No statistically significant associations were observed for low- or high-stage disease. The association for vasectomy was more pronounced in men who were 40 years at the time of vasectomy (HR=2.63; 95% CI 1.40–4.94) than in men who were younger at vasectomy. Conclusions The results from this prospective study suggest a positive association between vasectomy and prostate cancer, especially low-grade disease. Supported by National Cancer Institute Grant CA 08030, National Institute of Aging Grant AG18033, and Department of Defense Grant DAMD17-94-J-4265. Dr. Rohrmann is supported by the Fund for Research and Progress in Urology, Johns Hopkins Medical Institutions. Dr. Paltoo was supported by the Cancer Prevention Fellowship Program, Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, during the time she was working on this project. Dr. Comstock was partially supported by Research Career Award HL 21670 from the National Heart, Lung, and Blood Institute. These data were supplied in part by the Maryland Cancer Registry, the Department of Mental Hygiene, Baltimore, Maryland. The Department of Health and Mental Hygiene specifically disclaims responsibility for any analyses, interpretations or conclusions.