trans-Nonachlor and cis-nonachlor toxicity in Sprague-Dawley rats: comparison with technical chlordane.

cis-Nonachlor and trans-nonachlor are bioaccumulating components of the pesticide chlordane, which can be detected in various environmental biota and in humans. Existing studies have focused on the potential adverse health effects of the parent chlordane mixture. Comparable toxicity data are nonexistent for individual chlordane constituents such as trans-nonachlor, cis-nonachlor, or oxychlordane, which are among the most common chlordane-related environmental contaminants and tissue residues. In this study, rats were administered cis-nonachlor, trans-nonachlor, or technical chlordane by gavage for 28 days at doses of 0.25 to 25 mg/kg body weight. Residue analyses indicated that trans-nonachlor accumulation in adipose was greater than cis-nonachlor when rats were administered each chemical under identical conditions of dose and exposure. For all test chemicals, the major metabolite oxychlordane accumulated in adipose tissue. Adipose tissue residue levels of all test chemicals and the major metabolite were higher in female rats. The liver was a target organ in male and female rats, indicated by increased liver weight and histopathological changes consistent with microsomal enzyme induction. Hepatic changes were most pronounced in rats treated with trans-nonachlor. Elevated kidney weights and depressed organic ion transport were observed in males treated with trans-nonachlor and chlordane. Although in general, changes in target organs and clinical chemistry endpoints were similar for all 3 test chemicals, the approximate toxicity ranking from most to least toxic was trans-nonachlor > technical chlordane > cis-nonachlor.

PCB congener patterns in rats consuming diets containing Great Lakes salmon: analysis of fish, diets, and adipose tissue.

As part of a multidisciplinary toxicological investigation into Great Lakes contaminants, chinook salmon were collected from Lake Huron (LH) and Lake Ontario (LO) and incorporated (as lyophilized fillets) into standard rat diets as 20 or 100% of the protein complement (5 or 20%, w/w diet-LH5, LH20, LO5, and LO20 diets). Final PCB concentrations in the experiment ranged from 3.15 ng/g in the control diet to 1080 ng/g in the high-dose (20%) LO diet, with maximal estimated daily consumption by the rats of 82microg PCBs/kg body wt in the LO20 dietary group. Seventeen PCB congeners, PCB 85, 99, 101, 105, 110, 118, 128, 129, 132, 138, 149, 153, 170, 177, 180, 187, and 199, occurred at >/=3.0% of the total PCBs in the fish with no major site differences. Cumulatively, these 17 congeners accounted for up to 75% of the total PCBs in the fish compared to 44 and 54% in two commercial Aroclors, 1254 and 1260, respectively. PCB 77 was the major "dioxin-like" congener in the fish, followed by PCB 126 and then PCB 169. All major dietary congeners bioaccumulated in the adipose tissue of the rats with the exception of PCB congeners 101, 110, 132, and 149. The group of 17 major congeners accounted for up to 71% of the total PCBs in adipose tissue samples collected from the rats following up to 19 weeks of diet ingestion. Of the coplanar PCB congeners, PCB 77 appeared to bioaccumulate to a lesser extent compared to PCBs 126 and 169. When comparing PCBs in the rat adipose tissue to PCB congeners in Canadian breast milk, PCBs 44, 49, 74, and 137 tended to occur in higher amounts in the human samples (contributing together 18.4 vs. 1.4% of the total PCB concentration), whereas PCB 129 occurred at higher levels in the rats (3.4 vs. 0.3% of the total PCB concentration, respectively). Although adipose tissue from the rats fed diets containing Great Lakes salmon had up to two orders of magnitude higher concentrations of PCBs compared to average human values, with the exception of some lower chlorinated congeners, similar major congeners tended to be present in both the rats in the present study and humans.

Report of the WHO working group on the assessment of health risks for human infants from exposure to PCDDs, PCDFs and PCBs.

On Nov. 20-22, 1995, a World Health Organization working group consisting of 12 scientific representatives from 6 different countries met to reassess the health risks to infants associated with perinatal exposure to polyhalogenated aromatic hydrocarbons (PHAHs). Following a review of previous WHO/EURO consultations, as part of their comprehensive programme on PCDDs, PCDFs and PCBs, current exposure information and recent experimental and epidemiologic data were discussed. Exposure assessments within the past decade have revealed that in the case of breast milk samples concentrations of PCDDs/DFs and PCBs have shown a continual decline, in certain countries by up to 50%. New experimental data has revealed that a variety of structural, functional and behaviourial alterations can be induced in rodent species following exposure to PHAHs while a Dutch collaborative PCB/dioxin study has illustrated subtle clinical, endocrine and mental/psychomotor development effects can occur in breast fed infants. The provisional conclusions of the working group were: 1) current evidence does not warrant altering the previous WHO recommendation for promotion/support of breast feeding and 2) based on new clinical data which supports the biological plausibility of certain observed experimental observations, continued and enhanced effort should be directed towards identifying and controlling sources of environmental input for these contaminants.

Dietary and tissue residue analysis and contaminant intake estimations in rats consuming diets composed of Great Lakes salmon: a multigeneration study.

To further characterize the toxicological risk associated with chemical contaminants in Great Lakes fish, a multigeneration rat reproduction study was designed. Mature chinook salmon (Oncorhynchus tsawytscha), collected during the Fall 1991 spawning runs from Sydenham River, Lake Huron, and Credit River, Lake Ontario, were filleted, lyophilized, and incorporated into standard rat diets at 25% (w/w) or 100% (w/w) of the normal protein compliment [casein, 20% (w/w)]. This resulted in diets composed of 5 or 20% (w/w) lyophilized fish and estimated daily fish intakes by the rats at levels approximately 15- and 60-fold greater, respectively, than the current estimate for the Canadian public for all fish and seafood. Both fresh and lyophilized fish were analyzed for the following groups of contaminants: halogenated aromatic hydrocarbons [polychlorinated biphenyls, dibenzodioxins, and dibenzofurans (PCBs, PCDDs, PCDFs)], polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, metals, volatile organics, and other extractable organics (chlorinated phenols and benzenes). In general, only minor site differences existed for the specific types of contaminants detected; however, fish from the Credit River contained slightly greater amounts of PCBs (2- to 3-fold), dioxin toxic equivalencies (TCDD TEQs; 1.5- to 2.0-fold), DDT and metabolites (1. 5-fold), and appreciably higher amounts of mirex (15-fold). This general pattern of contaminant differences continued when the various diets were prepared using the lyophilized fish. Tissue samples (adipose, liver) were taken from the animals at various stages of the study and also analyzed for the same groups of contaminants. In general, adipose tissue was the major reservoir for organochlorine (OC) pesticides and PCBs, while "dioxin-like" PCDD/DF congeners and mercury were found preferentially in the liver. Contaminant intake calculations and tissue residue levels are provided.

The health Canada Great Lakes multigeneration study--summary and regulatory considerations.

The Health Canada Multigeneration Study was initiated to determine the consequences in rodents consuming diets containing Lake Ontario (LO) or Lake Huron (LH) chinook salmon over successive generations. Following lyophilization, the contaminant levels in the salmon used in the formulation of the diets for this study exceeded a number of tolerances or guidelines established for contaminants in commercial fish and seafood products (PCBs, dioxin, mirex, chlordanes, mercury). Consumption of the fish diets by rats of two consecutive generations resulted in a variety of effects that can be described as adaptive responses or of limited biological significance. The two exceptions to this were (1) the suggestion of modification of working and reference memory in males of the high-dose groups 20% fish diets, which may have been related to decreases noted in neurotransmitters in several brain regions in these rats; and (2) an effect on thymus weights noted in the high-dose first generation (F1) reversibility study animals and an overall effect on T-helper/inducer lymphocyte subset numbers in the second generation (F2) male rats fed the LH diets compared to the LO diets. Relatively minor effects were observed in the rats consuming the 5% fish diets from either Great Lakes location (LH-5, LH-5), although their fish intake was approximately 16-fold greater on a daily basis than the average angler consuming Great Lakes sport fish (compared to a 60-fold greater intake in the 20% diet groups: LH-20, LO-20). Based on these study results with rats it would appear that for the average consumer of Great Lakes sports fish, the risk presented by the complex mixture of contaminants in chinook salmon collected from these two locations in the Great Lakes basin could be considered minimal, especially if sport fish consumption advisories are followed.

Binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to AH receptor in placentas from normal versus abnormal pregnancy outcomes.

Binding of [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin to AH receptor was characterized in cytosol from human placentas in which the pregnancy outcome was normal compared with pregnancies in which there was some adverse outcome (premature birth; intrauterine growth retardation; structural abnormality). No significant difference was detected between normal and adverse outcomes in the concentration of AH receptor sites (Bmax) nor in the affinity with which [3H]TCDD bound to the receptor (Kd). Aryl hydrocarbon hydroxylase activity, a CYP1A1 enzyme regulated by the AH receptor, was elevated in placental microsomes from smokers; this elevation was associated with intrauterine growth retardation.

Biomarkers for Great Lakes priority contaminants: halogenated aromatic hydrocarbons.

One of the major goals of the Great Lakes Action Plan is to actively accumulate and assess toxicological information on persistent toxic substances found in the Great Lakes basin. As part of Health Canada's commitment to this plan, a review of biomarkers for the environmental contaminants polychlorinated biphenyls (PCBs) and polychlorinated dibenzodioxins/dibenzofurans (PCDDs/PCDFs) was conducted. In general, while food consumption was identified as the major source of human exposure to both contaminant groups, certain commodities, such as fish, milk and dairy products, and meat, were found to predominate. Due to the ubiquitous nature of these environmental contaminants and their propensity to bioaccumulate, all humans will have detectable body burdens, which in certain cases can be positively associated with the consumption of particular foods (i.e., PCBs and freshwater fish from the Great Lakes). When dealing with environmental exposure only, relating specific effect biomarkers to contaminant exposure or tissue levels was difficult, due in part to the complex nature of the exposure and the nonspecific nature of the effect. For PCBs, the most likely biomarkers of effect included some form of alteration in lipid metabolism (serum triglyceride/cholesterol levels) and elevation of hepatic-related enzymes, aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT). Cross-species extrapolation also indicates the potential for neurotoxicologic effects to occur in humans. For PCDDs/PCDFs, dermatologic lesions (chloracne) and indications of hepatic enzyme induction have been documented, but primarily due to occupational or high acute accidental exposures. Recent evidence suggests that neonates may represent a potential at-risk population due to relatively high exposure to PCDDs/PCDFs, as with PCBs, during breast feeding as compared to standard adult dietary intake. Future areas of potential benefit for biomarker development include immunologic and endocrine effects, primarily based on biologic plausibility from experimental animal research.

Workshop on perinatal exposure to dioxin-like compounds. III. Endocrine effects.

Studies involving endocrine effects in humans and experimental animals resulting from the exposure to dioxin-like (non-ortho-substituted PCBs, PCDDs/PCDFs) and nondioxin-like (PCBs, OC pesticides) compounds (DLCs and NDLCs) were presented. A variety of reproductive and hormonal parameters, including androgen status, sexual differentiation, and thyroid functionality, were discussed. As in utero and lactational exposure of the human fetus/neonate to these environmental contaminants is inevitable, continued research to identify sensitive biomarkers of effect and susceptibility, as well as to define dose-response relationships, is required.

Hyperthermia radiosensitization in human glioma cells comparison of recovery of polymerase activity, survival, and potentially lethal damage repair.

PURPOSE: DNA polymerase inactivation is compared to thermal radiosensitization and inhibition of damage recovery in human glioma cells. METHODS AND MATERIALS: Two human glioma cell lines (U87MG and U373MG) were exposed to hyperthermia and irradiation. Hyperthermia was given at 43 degrees C and 45 degrees C and DNA polymerase alpha + delta + epsilon and beta activities were measured. Hyperthermia was given at various times before irradiation and the degree of radiosensitization and polymerase activity was assessed at various times after heating. In addition the ability of cells to undergo repair of potentially lethal radiation damage was assessed for cells irradiated at various times after heating. RESULTS: Polymerase alpha + delta + epsilon and polymerase beta both recovered after heating but polymerase beta was faster and was complete in U373MG but not in the U87MG cell lines after 48 h incubation after heating (45 degrees C, 60 min). Incubation, between hyperthermia and irradiation resulted in a loss of radiosensitization and a loss of inhibition of repair of potentially lethal damage. These changes correlated well with recovery of polymerase beta but not with polymerase alpha + delta + epsilon. CONCLUSION: The correlation of polymerase beta activity and thermoradiosensitization and its recovery indicate that polymerase beta may be one of the mechanisms involved in thermoradiosensitization.

Approach to risk assessment of PCDDs and PCDFs in Canada.

The nongenotoxic classification for the ubiquitous environmental contaminants polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) implies that a toxicity threshold may exist. Therefore, a minimal risk level or tolerable daily intake (TDI) value can be estimated by identifying no observable adverse effect levels (NOAELs) from animal toxicological investigations and extrapolating this dose to humans by the use of safety factors. When available, data from epidemiological investigations are utilized and carry a larger "weighting" than the animal studies (i.e., smaller safety factors required). A complete database review for the most toxic congener of this class of halogenated aromatic hydrocarbons, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), yields a NOAEL of 1.0 ng/kg body wt/day for rat carcinogenicity (Kociba et al., Toxicol. Appl. Pharmacol. 46, 279-303, 1978) and reproductive toxicity (Murray et al., Toxicol. Appl. Pharmacol. 50, 241-252, 1979) effects. By employing a 100-fold safety factor to compensate for inter- and intraspecies variability, a tentative TDI value can be estimated at 10 pg/kg body wt/day. For food intake purposes, a total of 17 2,3,7,8-substituted PCDD/PCDF congeners are included in this estimate by using an additive toxic equivalency (TEQ) approach based on international toxic equivalency factors (I-TEFs) developed by NATO (NATO Report No. 178, 1988). This implies that averaged over an individual's total lifespan (estimated at 70 years), 600 pg TCDD TEQs can be taken in daily (60 kg average body weight) without appreciable risk of deleterious effects. The current estimated Canadian daily intake for PCDDs and PCDFs from all sources is 2.0-4.2 pg TCDD TEQs/kg body wt/day (Gilman et al., Chemosphere 23, 1661-1667, 1990). Recent comprehensive epidemiological studies involving industrial/occupational scenarios suggest an increased cancer risk for workers exposed to TCDD-contaminated processes (products contaminated with TCDD) but only at relatively high exposure levels with long latency periods when compared to the background population. To date, the only sustained toxic effect in humans associated with PCDD/PCDF exposure has been chloracne and related dermatological lesions.

A comparison of the enhancement of radiation sensitivity and DNA polymerase inactivation by hyperthermia in human glioma cells.

Two human glioma cell lines (U87MG and U373MG) were evaluated for their thermal enhancement of radiation sensitivity and its correlation to the degree of inactivation of DNA polymerase alpha and beta. The data showed that hyperthermia increased radiation sensitivity in a time- and temperature-dependent manner. The differential heat sensitivity of the two cell lines was reflected in the degree of polymerase inactivation. Polymerase inactivation was also dependent on time and temperature and was greater for polymerase beta than alpha. The degree of polymerase inactivation correlated well with the thermal enhancement ratio (TER) calculated at the 1.0% survival level. This correlation was poor for the TER at the 50% survival level. The correlations were better for polymerase beta than alpha. The small differences in thermal sensitivity between the two cell lines primarily at 41 and 42 degrees C could not be explained by correlation between polymerase inactivation and TER. Incubation between hyperthermia and irradiation resulted in recovery of polymerase activity and loss of radiosensitization. Levels of polymerase beta after hyperthermia may be used to predict thermal enhancement of radiosensitivity for low survival levels, but possibly not in the shoulder region of the radiation survival curve. Small cell line-dependent differences in thermal sensitivity may not be resolved in these comparisons.

A comparison of the effect of hyperthermia on DNA polymerase in hamster and human glioma cells.

The hyperthermia response of two human glioma cells lines (87MG and 373MG) was compared to the CHO cell line for cell killing and DNA polymerase inactivation. Glioma cells were found to be more thermally resistant than CHO cells over a temperature range of 41-46 degrees C. Inactivation of polymerase alpha and beta by hyperthermia was also more resistant in glioma cells than in CHO cells. The relative order of resistance for both killing and polymerase inactivation was 373MG > 87MG > CHO. While polymerase inactivation correlated with cell killing at high thermal doses, such correlation at low doses was absent; i.e. thermal killing was characterized by survival curves with shoulders while polymerase inactivation was not. Thus at low thermal doses the mechanism of thermal cell killing is probably not related to the degree of polymerase inactivation. Arrhenius analysis of the survival data showed that the inactivation energy for the glioma cells was 133-135 kcal/mol. The inactivation energies of alpha and beta polymerase were also evaluated and were 102-104 and 140-146 kcal/mol, respectively. Further analysis of the temperature-time relationship of hyperthermia treatment resulting in 50% cell kill showed the degree of polymerase beta inactivation to be a good indicator of thermal dose.

Changes in survival and potentially lethal damage recovery following periods of high and low metabolic activity in human glioma cells.

Radiation survival and recovery from potentially lethal damage has been measured in human glioblastoma cells as they progressed from an exponential to an extended plateau growth phase. Immediate plating (IP) survival following 7.5 Gy 60Co irradiation decreased from 2.3% for cells in exponential growth phase to 0.11% for cells held in an extended plateau growth phase with no change or adjustments made to the medium. Delayed plating (DP) survival decreased from 10% to 2.5%, respectively. Under these conditions, medium pH, rate of glycolysis, and proliferation status were monitored. IP survival was found to be sensitive to both proliferation status and the amount of time the cells spent in a metabolically quiescent state. Recovery ratios (DP surv./IP surv.) increased from 4.3 to 23, primarily due to IP survival decreasing at a greater rate than DP survival. Aerobic glycolysis was found to be responsible for approximately 42% of the glucose utilization. Metabolic activity (glycolysis) was increased by increasing the pH of the existing medium. Survival was measured 3 days after each pH adjustment to allow a new metabolic equilibrium to establish with a pH and rate of glycolysis comparable to that in control experiments that had no pH adjustments. Both IP and DP survival showed only slight decreases compared to control experiments, while the recovery ratio at the end of a 6-day plateau period remained the same as in control experiments. No additional cell growth or redistribution of cells within the cell cycle occurred. Thus a period of increased metabolic activity prior to irradiation is advantageous for both IP and DP survival as compared to a period of low metabolic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of heat sensitivity, radiosensitivity and PLDR in four human melanoma cell lines.

Comparison of the heat sensitivity and radiosensitivity of four human melanoma cell lines in culture revealed a large variation in sensitivity amongst the four cell lines. Three of the four cell lines had large shoulders on the survival curves when exposed to hyperthermia (44 degrees C or 45 degrees C). These three cell lines also had demonstrable shoulders on the acute radiation dose response curves. The most radiosensitive cell line did not show a shoulder region in the heat or radiation survival curves (HT-144, Dq = 0.2 Gy). Despite this consistency in the presence or absence of shoulder, there was no correlation between heat and radiation sensitivity in the four melanoma cell lines. Furthermore, regardless of radiosensitivity, all four lines studied showed competent repair of potentially lethal damage. The recovery ratios at a surviving fraction of 0.001 ranged from 5.7 to 7.6. All four lines had a similar cell cycle distribution at the time of treatment, hence the variation observed in the response of these four lines to radiation and heat was not due to differences in cell cycle kinetics. Preliminary results of DNA polymerase-alpha and -beta activities do not demonstrate a clear correlation between cellular levels of these two enzymes and radiosensitivity.

Enhancement of sensitivity to hyperthermia by lonidamine in human cancer cells.

Human glioma (87MG) and squamous cell carcinoma of the head and neck UMSCC-1 were shown to be sensitized to hyperthermia by Lonidamine treatment before and during hyperthermia. The degree of thermal sensitization increased with increasing heating times and temperatures. In addition, the thermal sensitization by Lonidamine as well as cellular thermal sensitivity were dependent on pH and increased with the more acidic pH. Even though plateau phase cells were more thermally resistant than exponentially growing cells, Lonidamine treatment caused thermal sensitization under both conditions. These data show that Lonidamine may hold potential to enhance the effectiveness of hyperthermia in cancer treatment and that especially in tumours with low pH an enhanced therapeutic gain may be achieved.

Hyperthermia enhancement of radiation response and inhibition of recovery from radiation damage in human glioma cells.

Three human glioma cell lines were tested for the effectiveness of hyperthermia and thermal radiosensitization. Thermal sensitization was evaluated from the perspective of increased radiosensitivity as well as inhibition of recovery from radiation damage. The three glioma cell lines tested showed large shoulders on the radiation survival curve and a large capacity for recovery of potentially lethal radiation damage. Hyperthermia caused radiosensitization in all three cell lines, which was primarily characterized by the reduction of the survival curve shoulder with moderate decreases in the survival curve slope. The radiosensitization was dependent on the time and temperature of the hyperthermia treatment. At 45 degree C for 60 min the shoulder of the radiation survival curve could be completely eliminated and the degree of enhanced cell killing at the 2 Gy level ranged from factors of 10 to 20 under the various conditions. When hyperthermia was given to cells which were irradiated and then plated immediately, or delayed for 8 h before plating to allow recovery, hyperthermia was found to cause radiosensitization under both conditions. In addition, when the hyperthermia dose was increased the difference between the immediate plating and the delayed plating survival curve decreased and for 45 degrees C for 60 min this difference was completely eliminated, concomitantly with the elimination of the survival curve shoulder. These data indicate that hyperthermia may play a role in radiosensitization for the treatment of human glioma.

The effect of lonidamine (LND) on radiation and thermal responses of human and rodent cell lines.

Rodent and human cells were tested for response to Lonidamine (LND) (1-(2,4 dichlorobenzyl) 1-indazol-3-carboxylic acid) combined with radiation or hyperthermia. Lonidamine exposure before, during, and after irradiation caused varying degrees of inhibition of potentially lethal damage (PLD) repair which was cell line dependent. In human glioma, melanoma, squamous cell carcinoma, and fibroblasts, LND exposure did not inhibit or only partially inhibited repair of potentially lethal damage. LND up to 100 micrograms/ml produced only a low level of toxicity in these cells and only slightly inhibited glucose consumption at the maximum concentration. In human glioma cells, LND treatment alone did not inhibit PLD repair, but when combined with hyperthermia treatment at moderate levels easily achievable in the clinic, there was complete inhibition of potentially lethal damage repair. These data suggest that LND effectiveness is cell type dependent. Combinations of LND, hyperthermia, and radiation may be effective in cancer therapy especially in tumors such as glioma in which repair of potentially lethal damage may be extensive.

The effect of lonidamine alone and in combination with cisplatin on in vitro growth and viability of lung squamous cell carcinoma cell lines.

Two non small cell lung cancer (NSCLC) cell lines were tested in vitro to evaluate the effect of lonidamine, cisplatin and combinations of these two agents using different doses and schedules. Lonidamine alone at concentrations greater than 50 micrograms/ml caused inhibition of cell growth in both monolayer and spheroid cell cultures. Cisplatin at concentrations of 10-20 microM caused a concentration dependent toxicity and inhibited growth in monolayer and spheroid cell cultures. Combination treatment of lonidamine and cisplatin caused concentration dependent effects. For 25 micrograms/ml lonidamine, there was no additive and in some cases an antagonistic effect when used with cisplatin. For higher lonidamine concentrations (75 and 100 micrograms ml), an additive effect with cisplatin (10-15 microM) was observed. This effect saturated for cisplatin concentrations of 20 microM. These data show some potential for lonidamine and cisplatin combination therapy but treatment doses and schedules will have to be identified so that the additive effect can be achieved at concentrations clinically attainable.

The in vitro effects of lonidamine combined with cisplatin in human small cell lung cancer cell lines.

Two human small cell lung cancer (SCLC) cell lines were used to evaluate the in vitro response to lonidamine and cisplatin exposure. The two cell lines both showed growth inhibition when exposed to lonidamine alone at concentrations greater than 50 micrograms/ml; however, one cell line (H69) was more sensitive. When cisplatin was combined with lonidamine a synergistic interaction was observed when cells were exposed to 10 microM cisplatin for 1 hour combined with lonidamine at concentrations of 50 micrograms/ml or greater. At a concentration of 25 micrograms/ml lonidamine combined exposure with cisplatin had no effect on cell growth or viability.

Lonidamine can enhance the cytotoxic effect of cisplatin in human tumour cells and rodent cells.

Lonidamine combined with cisplatin treatment was tested in human glioma (U87MG) human squamous cell carcinoma (UMSCCl) and Chinese hamster (HA1) cells. The order of sensitivity to cisplatin was HA1 greater than U87MG greater than UMSCCl. Lonidamine caused little sensitization in U87MG cells, moderate sensitization in HA1 cells and large sensitization in UMSCCl cells. The degree of sensitization was correlated to the effect of lonidamine on cell growth. The degree of sensitization to cisplatin by lonidamine treatment was dependent on lonidamine exposure concentration, time and treatment sequence. Lonidamine shows potential for enhancement of cisplatin chemotherapy but this appears to be cell type specific and should be tested for cells derived from sites of clinical interest for such drug therapy.