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PubMed1994

Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA binding in rats given chlorophyllin: dose-response and time-course studies in the liver and colon.

Chlorophyllin (CHL), a water-soluble salt of chlorophyll, has been shown to inhibit 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA binding in vitro by a mechanism that involves molecular complex formation with the carcinogen. Based on this mechanism, rats weighing approximately 160 g were given 10 mumol (100 microCi) IQ or IQ plus 20, 200 or 1000 mumol CHL by single oral gavage. Six hours after dosing, CHL produced dose-related inhibition of IQ-DNA binding in three target organs for carcinogenesis, namely, the small intestine, large intestine and liver. In the latter tissues, > 80% inhibition was detected at the highest CHL dose tested, while IQ-DNA binding levels in the small intestine were reduced to below the limit of detection. Co-injection of CHL and IQ into ligated sections of small intestine inhibited the absorption of IQ in a dose-related manner, such that the highest dose of CHL almost completely blocked carcinogen uptake. Finally, rats given CHL by gavage at time 0 h were treated with IQ at various times thereafter and IQ-DNA binding levels were measured in the liver and colon 6 h after carcinogen exposure. Compared with controls given IQ alone, CHL inhibited binding by 79% at 0 h and 40% at 1 h in the liver, and by 63% at 0 h, 38% at 1 h and 58% at 24 h in the colon (P < 0.05 by Student's t-test). These results support a mechanism involving complex formation between CHL and IQ in vivo and suggest that the inhibitor is likely to be most effective when ingested simultaneously with the carcinogen.

Animals↗
PubMed1995

Protection by chlorophyllin and indole-3-carbinol against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced DNA adducts and colonic aberrant crypts in the F344 rat.

The most abundant heterocyclic amine in fried ground beef, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), induces colon carcinomas in the male F344 rat. The potential chemopreventive effects of two compounds, namely, the 'interceptor molecule' chlorophyllin (CHL) and a modulator of carcinogen activation, indole-3-carbinol (I3C), were examined in a PhIP colon carcinogenesis model. During weeks 3 and 4 of a 16-week study, F344 rats were given PhIP by oral gavage (50 mg/kg body weight, alternating days). Inhibitors were given either before and during PhIP exposure, after PhIP treatment, or continuously for 16 weeks. Treatment of rats with 0.1% CHL in the drinking water inhibited the formation of aberrant crypt foci (ACF) with > or = 4 crypts/focus, from 1.4 +/- 0.9 in controls to 0.7 +/- 0.3 following post-initiation CHL treatment, and to 0.3 +/- 0.5 in rats given CHL continuously for 16 weeks (mean +/- SD; P < 0.05). Potent inhibition of PhIP-induced ACF occurred following initiation, post-initiation and continuous exposure to 0.1% I3C in the diet. Using the initiation protocol, I3C completely inhibited the induction of the ACF with > or = 4 crypts/focus. In a separate experiment, rats were given 0.1% CHL in the drinking water or 0.1% I3C in the diet for 4 weeks. At the end of week 3, animals received 50 mg PhIP/kg body weight by single oral gavage and PhIP-DNA adducts were quantified in the colon and several other tissues by 32P-postlabeling analysis. In addition, the urine and feces were collected to study the effects of inhibitor treatment on PhIP metabolism and excretion. No significant protection against PhIP-DNA adduct formation was detected in the colon after CHL dosing, nor was a consistent pattern of CHL inhibition observed in several other tissues. In contrast, I3C shifted the time-course of adducts in all tissue; compared with controls, adducts were increased by I3C at 6 h but decreased at 24 h and 7 days following PhIP treatment. Analysis of urine metabolites revealed that I3C and CHL decreased the excretion of unmetabolized PhIP and 4'-hydroxy- << PhIP but increased the phase II detoxification products PhIP-4'-O-glucuronide and PhIP-4'- sulfate. In the feces, the elimination of unmetabolized PhIP was increased from 54.5% in controls to approximately 67% in CHL-treated rats and decreased to 28% in rats given I3C (P < 0.05). These results support a protective role for CHL and I3C against PhIP-induced colon carcinogenesis through mechanisms which alter the uptake or metabolism of the carcinogen, and by suppression in the post-initiation phase.

Animals↗
PubMed1995

Non-specific inhibition of cytochrome P450 activities by chlorophyllin in human and rat liver microsomes.

Chlorophyllin, a copper/sodium salt of chlorophyll used in the treatment of geriatric patients, inhibits the mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 3-amino-1-methyl-5H- pyrido[4,3-b]indole (Trp-P-2), aflatoxin B1 and benzo[a]pyrene (B[a]P). Recent in vitro and in vivo studies have shown that a molecular complex is formed between IQ and chlorophyllin, suggesting that this complex formation might be responsible for the antigenotoxic effect of chlorophyllin observed. Cytochrome P450 (P450) enzymes appear to be the major catalysts in the bioactivation of these carcinogens. We have investigated the in vitro effects of chlorophyllin on several P450 activities including ethoxyresorufin O-deethylation, benzyloxyresorufin O-debenzylation, coumarin 7-hydroxylation, 7-ethoxycourmarin O-deethylation, B[a]P 3-hydroxylation, and chlorzoxazone 6-hydroxylation. Chlorophyllin non-specifically inhibited all of P450 activities observed. Spectrally detectable P450 was also destroyed in microsomes and purified P450 in a reconstituted system in the presence of chlorophyllin and an NADPH-generating system. These results suggest that the antigenotoxic effect of chlorophyllin might be due to inhibition of P450 enzymes involving bioactivation of carcinogens in addition to molecular complex formation between carcinogens and chlorophyllin. Comparison of the apparent Ki for P450 inactivation with previously estimated constants for chlorophyllin-IQ complexation suggest that P450 inhibition should be the dominant mechanism of inhibition.

Animals↗
PubMed1995

Inhibitory effect of chlorophyllin on PhIP-induced mammary carcinogenesis in female F344 rats.

Chlorophyll and chlorophyllin, a water-soluble salt of chlorophyll, have been reported to inhibit carcinogen-DNA binding and exert antimutagenic activity for some carcinogenic heterocyclic amines and aflatoxins. In the present experiment, the possible inhibitory effects of chlorophyllin on 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) carcinogenicity were investigated. Female F344 rats were administered both PhIP, 0.02% in the diet, and chlorophyllin, 1%, in the diet (group 1), or either PhIP (group 2) or chlorophyllin (group 3) alone for 54 weeks. The incidence of mammary adenocarcinomas induced by PhIP was reduced by chlorophyllin co-administration from 40% (8/20 rats) to 15% (3/20). While the difference was not statistically significant, the multiplicity of adenocarcinomas was significantly (P < 0.05) reduced by chlorophyllin co-administration from 0.50 per animal to 0.15. On the other hand, incidence of colon adenomas was slightly, but not significantly, increased from 10% to 20%. Neither mammary nor colon adenocarcinomas were observed in group 3. Thus, chlorophyllin reduced PhIP mammary carcinogenesis, suggesting that chlorophyllin is an effective chemopreventor when ingested simultaneously with the carcinogen.

Animals↗
PubMed1996

Modulatory influence of chlorophyllin on the mouse skin papillomagenesis and xenobiotic detoxication system.

The present study evaluates the modulatory potential of chlorophyllin (CHL) on the murine skin papillomagenesis pattern and its influence on the levels of biotransformation system enzymes. Topical application of CHL (100 mg/kg body weight/day) during peri-, post- or peri- and post-initiational stages of 7,12-dimethylbenz[a]anthracene (DMBA)-induced papillomagenesis, significantly (P < 0.01) reduced the (i) tumor burden to 3.68, 3.56 and 3.33 (positive control value: 5.89); (ii) cumulative number of papillomas to 59, 57 and 60 (positive control value: 112); and (iii) incidence of mice bearing papillomas to 88%, 88% and 90%, respectively (positive control value 100%). CHL treatment alone or during peri-, post-, or peri- and post-initiational stages significantly elevated the glutathione S-transferase (GST) and -SH levels in the liver and skin tissue of the murine system. The potential of CHL in modulating the process of carcinogenesis is suggested by the altered levels of biotransformation system enzymes. The implications of the biochemical changes and inhibition of tumor incidence by CHL are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Distribution and metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in female rats and their pups at dietary doses.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary carcinogen in female rats and is present in a wide variety of cooked meats. We address here the excretion of PhIP and its metabolites into the breast-milk of lactating rats and the ability of chlorophyllin, a food product derivative with chemopreventive properties, to affect these levels at low PhIP doses. Lactating female F344 rats with suckling pups were orally administered 50, 500 and 1000 ng [14C]PhIP/kg body weight. The excretion of the [14C]PhIP into milk and its distribution among the mammary tissue, liver and blood of the dam, as well as among stomach contents and liver of their suckling pups was measured using accelerator mass spectrometry (AMS). PhIP, PhIP-4'-sulfate, 4'-hydroxy-PhIP, and N2-hydroxy-PhIP-N3-glucuronide were found in the milk at all doses. The chlorophyllin (500 microg/kg) co-administration with PhIP (500 ng/kg) caused increased levels of [14C]PhIP in the milk (32%) and stomach contents (35%) of the pups relative to the animals not receiving chlorophyllin at these low PhIP doses. In contrast, lower [14C]PhIP levels in the chlorophyllin treated animals were observed in the blood (47%) and mammary tissue (68%) of the dam, as well as the pup's liver tissue (37%) compared to the animals receiving only PhIP. Chlorophyllin co-administration resulted in an increased amount of N2-hydroxy-PhIP-N3-glucuronide (42%), increased PhIP (79%) and decreased levels of PhIP-4'-sulphate (77%) relative to the animals not receiving chlorophyllin. These results suggest that PhIP and PhIP metabolites are present in the breast-milk of lactating rats at human dietary PhIP exposures and that PhIP is absorbed by the newborn. Furthermore, these results suggest that other dietary components can affect the dosimetry of PhIP in breast-feeding offspring.

Administration, Oral↗
PubMed1999

Inhibition of dibenzo[a,l]pyrene-induced multi-organ carcinogenesis by dietary chlorophyllin in rainbow trout.

Cancer chemoprevention by dietary chlorophyllin (CHL) was investigated in a rainbow trout multi-organ tumor model. In study 1, duplicate groups of 130 juvenile trout were treated for 2 weeks with control diet, 500 p.p.m. dibenzo[a,l]pyrene (DB[a,l]P) or 500 p.p.m. DB[a,l]P + 2052 p.p.m. CHL, then returned to control diet. DB[a,l]P alone proved somewhat toxic but induced high tumor incidences in liver (61%), stomach (91%) and swimbladder (53%) 11 months after initiation. CHL co-feeding abrogated DB[a,l]P acute toxicity and reduced tumor incidences to 18% in liver, 34% in stomach and 3% in swimbladder (P </= 0.01). A second tumor and DNA adduct study using a non-toxic initiation protocol (200 p.p.m. DB[a,l]P +/- 4000 p.p.m. CHL for 4 weeks) confirmed these results. Potential CHL inhibitory mechanisms were investigated. Dietary CHL inhibited hepatic DB[a, l]P-DNA adducts in the two tumor studies by 89 and 76%, respectively. CHL was shown to complex strongly with DB[a,l]P (K(d1,2) = 1.59 +/- 0.01 microM, stoichiometry 2CHL:DB[a,l]P) and strongly inhibited DB[a,l]P mutagenesis in the Salmonella assay. Significant inhibition occurred at CHL concentrations substantially less than stoichiometric with DB[a,l]P and thus not reflecting simple DB[a,l]P sequestration via complexation. These initial findings suggest that CHL chemoprevention reflects complexation that might limit DB[a,l]P uptake in vivo, antimutagenic mechanisms such as catalytic degradation of the proximate electrophile in target cells, or both. These results demonstrate that dietary CHL is a reproducibly effective chemopreventive agent for DB[a,l]P multi-organ tumorigenesis in trout and suggest that reduced DB[a,l]P-DNA adducts may be predictive biomarkers of CHL reduction of DB[a,l]P-initiated hepatic tumors.

Animals↗
PubMed2001

Post-initiation effects of chlorophyllin and indole-3-carbinol in rats given 1,2-dimethylhydrazine or 2-amino-3-methyl- imidazo.

Chlorophyllin (CHL) is a water-soluble derivative of chlorophyll, the ubiquitous pigment in green and leafy vegetables, whereas indole-3-carbinol (I3C) is present in cruciferous vegetables such as cabbage, broccoli and cauliflower. In rats initiated with 1,2-dimethylhydrazine (DMH), CHL and I3C reportedly promoted or enhanced the incidence of colon tumors when they were administered after, or during and after the carcinogen exposure, respectively. The same compounds given post-initiation inhibited the formation of colonic aberrant crypts induced by heterocyclic amines, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), but tumor suppression was not examined in the latter studies. In the present investigation, male F344 rats were treated with IQ or DMH during the first 5 weeks of a 1 year study; IQ was given in the diet (0.03%), whereas DMH was administered once a week by s.c. injection (20 mg/kg body wt). Beginning 1 week after the last dose of IQ or DMH until sacrifice, rats received 0.001, 0.01 or 0.1% (w/v) CHL in the drinking water or 0.001, 0.01 or 0.1% I3C in the diet. Compared with controls given carcinogen alone, 0.1% I3C treatment suppressed the multiplicity of IQ-induced colon tumors, and CHL inhibited in a dose-related manner the incidence of IQ-induced liver tumors. However, 0.001% CHL increased significantly the multiplicity of DMH-induced colon tumors while having no effect on the colon tumors induced by IQ. These results indicate that both the choice of carcinogen as well as the dose of the tumor modulator can be important determinants of the events that occur during post-initiation exposure to CHL or I3C. Based on the present findings and data in the literature, it is possible for CHL and I3C to act as tumor promoters or anticarcinogens, depending upon the test species, initiating agent and exposure protocol.

1,2-Dimethylhydrazine↗
PubMed2001

beta-Catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol.

Carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 1,2-dimethylhydrazine (DMH) induce colon tumors in the rat that contain mutations in beta-catenin, but the pattern of mutation differs from that found in human colon cancers. In both species, mutations affect the glycogen synthase kinase-3beta consensus region of beta-catenin, but whereas they directly substitute critical Ser/Thr phosphorylation sites in human colon cancers, the majority of mutations cluster around Ser33 in the rat tumors. Two dietary phytochemicals, chlorophyllin and indole-3-carbinol, given post-initiation, shifted the pattern of beta-catenin mutations in rat colon tumors induced by IQ and DMH. Specifically, 17/39 (44%) of the beta-catenin mutations in groups given carcinogen plus modulator were in codons 37, 41 and 45, and substituted critical Ser/Thr residues directly, as seen in human colon cancers. None of the tumors from groups given carcinogen alone had mutations in these codons. Interestingly, many of the mutations that substituted critical Ser/Thr residues in beta-catenin were from a single group given DMH and 0.001% chlorophyllin, in which a statistically significant increase in colon tumor multiplicity was observed compared with the group given DMH only. These tumors had marked over-expression of cyclin D1, c-myc and c-jun mRNA and c-Myc and c-Jun proteins were strongly elevated compared with tumors containing wild-type beta-catenin. The results indicate that the pattern of beta-catenin mutations in rat colon tumors can be influenced by exposure to dietary phytochemicals administered post-initiation, and that the mechanism might involve the altered expression of beta-catenin/Tcf/Lef target genes.

1,2-Dimethylhydrazine↗
PubMed2005

Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes.

Plant chlorophylls and carotenoids are highly colored, conjugated polyenes that play central roles in photosynthesis. Other porphyrins (tetrapyrroles), such as cytochromes, which are structurally related to chlorophyll, participate in redox reactions in many living systems. An unexpected new property of tetrapyrroles, including tetramethyl coproporphyrin III, tetrabenzoporphine, copper chlorin e4 ethyl ester, and of carotenoids including zeaxanthin and alpha-cryptoxanthin is their ability to induce mammalian phase 2 proteins that protect cells against oxidants and electrophiles. The capacity of these compounds to induce the phase 2 response depends upon their ability or that of their metabolites to react with thiol groups, a property shared with all other classes of phase 2 inducers, which show few other structural similarities. Pseudo second-order rate constants of these inducers are correlated with their potency in inducing the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in murine hepatoma cells. One of the most potent inducers was isolated from chlorophyllin, a semisynthetic water-soluble chlorophyll derivative. Although chlorophyll itself is low in inducer potency, it may nevertheless account for some of the disease-protective effects attributed to diets rich in green vegetables because it occurs in much higher concentrations in those plants than the widely studied 'phytochemicals'.

Animals↗
PubMed2006

The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between, dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers and final tumor outcome.

Chlorophyllin (CHL) is a potent antimutagen in vitro, an effective anti-carcinogen in several animal models, and significantly reduced urinary biomarkers of aflatoxin B(1) (AFB(1)) exposure in a human population. Here we report an expanded analysis of CHL chemoprevention using the potent environmental hydrocarbon dibenzo[a,l]pyrene (DBP). A dose-dose matrix design employed over 12 000 rainbow trout to evaluate the interrelationships among dietary carcinogen dose, anti-carcinogen dose, carcinogen-DNA adduct levels at exposure and eventual tumor outcome in two target organs. Included was an evaluation of the pharmaceutical CHL preparation (Derifil), used previously in a study of individuals chronically exposed to AFB(1). CHL was pre-, co- and post-fed at doses of 0-6000 p.p.m. and co-fed with DBP at doses of 0-371.5 p.p.m. for 4 weeks. This protocol generated a total of 21 dose-dose treatment groups, each evaluated with three or more replicates of 100 animals. The DBP-only treatment produced dose-responsive increases in liver and stomach DBP-DNA adducts, whereas increasing CHL co-treatment doses produced successive inhibition in liver (49-83%) and stomach (47-75%) adduct levels at each DBP dose examined. The remaining 8711 trout were necropsied, 10 months later. DBP treatment alone produced a logit incidence versus log [DBP] dose-response curve in stomach that was linear; CHL co-treatment provided dose-dependent tumor inhibition which ranged from 30 to 68% and was predictable from the adduct response. The Derifil CHL preparation was also found to effectively reduce DNA adduction and final tumor incidence in stomach (as well as liver), with a potency compatible with its total chlorin content. Liver tumor incidence in the DBP-only groups appeared to plateau near 60%. At DBP doses of <or=80 p.p.m., increasing CHL doses generally reduced tumor incidence and multiplicity consistent with early DNA adducts as biomarkers. At 225 p.p.m. DBP, however, very high CHL doses were required to reduce tumor incidence below the 60% plateau. Apparent tumor multiplicity in liver was neither linear nor monotonic with DBP dose, but peaked at 80 p.p.m. DBP and declined at 225 p.p.m., where it was increased by all but one CHL dose. Consequently, the effects of a given CHL dose and the predictivity of DNA adducts as biomarkers were highly dependent on carcinogen dose. These results underscore the critical importance of establishing carcinogen-end point dose-response relationships in chemoprevention studies, and the potential otherwise for misleading interpretations in chemoprevention studies carried out solely at high-carcinogen dose.

Animals↗
PubMed2002

Polycationic photosensitizer conjugates: effects of chain length and Gram classification on the photodynamic inactivation of bacteria.

OBJECTIVES: We have shown previously that a polycationic conjugate between poly-L-lysine and the photosensitizer chlorin(e6) was effective in photodynamic inactivation (PDI) of both Gram-positive and Gram-negative bacteria. In this report we explore the relationship between the size of the polylysine chain and its effectiveness for mediating the killing of Gram-negative and Gram-positive bacteria. METHODS: Conjugates were prepared by attaching precisely one chlorin(e6) molecule to the alpha-amino group of poly-(epsilon-benzyloxycarbonyl)lysines of average length eight and 37 lysine residues, followed by deprotection of the epsilon-amino groups, and were characterized by iso-electric focusing. The uptake of these conjugates and free chlorin(e6) by Gram-positive Staphylococcus aureus (ATCC 27659) and Gram-negative Escherichia coli (ATCC 29181) after washing was measured as a function of photosensitizer concentration (0-4 microM chlorin(e6) equivalent) and incubation time. After incubation the bacteria were exposed to low fluences (10-40 J/cm(2)) of 660 nm light delivered from a diode laser, and viability was assessed after serial dilutions by a colony-forming assay. RESULTS: S. aureus and E. coli took up comparable amounts of the two conjugates, but free chlorin(e6) was only taken up by S. aureus. After illumination S. aureus was killed in a fluence-dependent fashion when loaded with the 8-lysine conjugate and free chlorin(e6) but somewhat less so with the 37-lysine conjugate. In contrast, PDI of E. coli was only effective with the 37-lysine conjugate at concentrations up to 4 microM. PDI using the 8-lysine conjugate and free chlorin(e6) on E. coli was observed at a concentration of 100 microM. Transmission electron micrographs showed internal electron-lucent areas consistent with chromosomal damage. CONCLUSION: These results can be explained by the necessity of a large polycation to penetrate the impermeable outer membrane of Gram-negative E. coli, while Gram-positive S. aureus is more easily penetrated by small molecules. However, because S. aureus is more sensitive overall than E. coli the 37-lysine conjugate can effectively kill both bacteria.

Chlorophyllides↗
PubMed2004

The dietary phytochemical chlorophyllin alters E-cadherin and beta-catenin expression in human colon cancer cells.

Chlorophyllin (CHL), an anticarcinogenic and antimutagenic water-soluble derivative of chlorophyll, has been reported to induce apoptosis in human colon cancer cells via a pathway involving cell differentiation. Induction of differentiation markers may be important in limiting cancer-cell invasion and metastasis, and there is much interest in understanding the underlying mechanisms, because this might provide insights for cancer chemotherapy. In the present study, human HCT116 colon-cancer cells were treated with CHL, and the expression levels of E-cadherin and beta-catenin were examined using immunocytochemistry and laser scanning confocal microscopy. E-cadherin was detected almost exclusively at the cell periphery of cancer cells treated with or without CHL, but the expression of E-cadherin in the plasma membrane was markedly elevated in the cells treated with CHL. beta-Catenin also was strongly expressed in the plasma membrane, especially after CHL treatment. No change in the expression of beta-catenin mRNA was detected across a broad range of CHL concentrations (10-500 micromol/L), but there was a concentration-dependent decrease in nuclear beta-catenin protein levels without overt changes in the cytosolic pool of beta-catenin. Our interpretation of these findings is that CHL induces E-cadherin expression, and this facilitates trafficking of beta-catenin away from the nucleus and into the plasma membrane, possibly for destruction via the adherins junction remodeling (Hakai) pathway.

Biomarkers↗
PubMed2005

Natural chlorophyll but not chlorophyllin prevents heme-induced cytotoxic and hyperproliferative effects in rat colon.

Diets high in red meat and low in green vegetables are associated with an increased risk of colon cancer. In rats, dietary heme, mimicking red meat, increases colonic cytotoxicity and proliferation of the colonocytes, whereas addition of chlorophyll from green vegetables inhibits these heme-induced effects. Chlorophyllin is a water-soluble hydrolysis product of chlorophyll that inhibits the toxicity of many planar aromatic compounds. The present study investigated whether chlorophyllins could inhibit the heme-induced luminal cytotoxicity and colonic hyperproliferation as natural chlorophyll does. Rats were fed a purified control diet, the control diet supplemented with heme, or a heme diet with 1.2 mmol/kg diet of chlorophyllin, copper chlorophyllin, or natural chlorophyll for 14 d (n = 8/group). The cytotoxicity of fecal water was determined with an erythrocyte bioassay and colonic epithelial cell proliferation was quantified in vivo by [methyl-(3)H]thymidine incorporation into newly synthesized DNA. Exfoliation of colonocytes was measured as the amount of rat DNA in feces using quantitative PCR analysis. Heme caused a >50-fold increase in the cytotoxicity of the fecal water, a nearly 100% increase in proliferation, and almost total inhibition of exfoliation of the colonocytes. Furthermore, the addition of heme increased TBARS in fecal water. Chlorophyll, but not the chlorophyllins, completely prevented these heme-induced effects. In conclusion, inhibition of the heme-induced colonic cytotoxicity and epithelial cell turnover is specific for natural chlorophyll and cannot be mimicked by water-soluble chlorophyllins.

Animals↗
PubMed1999

Combination photoimmunotherapy and cisplatin: effects on human ovarian cancer ex vivo.

BACKGROUND: Patients with ovarian cancer that is clinically resistant to cisplatin-based chemotherapy have little hope of a cure of their disease. Photoimmunotherapy, which involves the antibody-targeted delivery of a nontoxic photosensitizer that is activated to a cytotoxic state with visible light, may offer a new treatment option. Photoimmunotherapy may be applied intraperitoneally to target disseminated tumor. We tested the hypothesis that this treatment in combination with cisplatin potentiates cytotoxicity in ovarian cancer cell lines and primary cultures of human tumors. METHODS: Five human cancer cell lines (ovarian and breast) and 19 primary cultures were studied. The primary cultures were from solid and ascites tumor samples obtained from 14 patients with ovarian cancer who were undergoing primary surgery. The photosensitizer chlorin e(6) was conjugated to the F(ab')(2) fragment of the murine monoclonal antibody OC-125, which is directed against the antigen CA 125. Cytotoxicity was measured by the microculture tetrazolium assay. Treatments consisted of cisplatin alone, photoimmunotherapy alone, and photoimmunotherapy followed by cisplatin. The fractional product method was used to assess synergy in treatment effects. Ex vivo cultured human cells exhibiting 80% or greater survival at cisplatin concentrations of 10 microM for 24 hours were defined as cisplatin resistant for this study. RESULTS: When all cell types (cisplatin sensitive and cisplatin resistant) were considered together, combination treatment yielded cytotoxicity that was, on average, 6.9 times (95% confidence interval = 1.86-11.94) greater than that of cisplatin alone (two-sided P =.023). Cisplatin-resistant cells showed a synergistic effect of the two treatments (two-sided P =.044), while cisplatin-sensitive cells showed an additive effect. CONCLUSION: These ex vivo data suggest that platinum resistance in human ovarian cancer cells may be reversible by pretreatment with OC-125-targeted photoimmunotherapy. Further studies are required to confirm the efficacy of this approach in vivo.

Antibodies, Monoclonal↗
PubMed1996

Protective effects of alpha-hederin, chlorophyllin and ascorbic acid towards the induction of micronuclei by doxorubicin in cultured human lymphocytes.

The influence of alpha-hederin (a saponin isolated from Hedera helix), chlorophyllin, the sodium-copper salt of chlorophyll, and ascorbic acid (vitamin C) on the direct clastogenicity of doxorubicin (Adriamycin) was investigated in vitro in human lymphocytes for the induction of micronuclei. In order to determine a possible mechanism of action responsible for the antimutagenic activity, treatments were performed for the three substances at different times of the culture (pre-treatment, simultaneous and post-treatment). Alpha-hederin (1.3 x 10(-2), 0.13, 1.3 and 13 nmol/ml) and chlorophyllin (0.14, 1.4 and 14 nmol/ml) were found to exert an antimutagenic effect against the clastogenicity of doxorubicin (1.5 x 10(-2) nmol/ml) in all treatments at all concentrations. Ascorbic acid (10 nmol/ml) was effective in reducing the micronucleus levels only in the simultaneous treatment, when it was previously incubated with doxorubicin for 2 h at 37 degrees C before being introduced into the culture. Our results suggested a desmutagenic effect for alpha-hederin, chlorophyllin and ascorbic acid. Chlorophyllin acted also through a bio-antimutagenic mechanism and alpha-hederin seemed to induce metabolic enzymes, which inactivated doxorubicin. Preliminary studies showed that the effective antimutagenic concentrations of alpha-hederin, chlorophyllin and ascorbic acid had no clastogenic or aneugenic effects in human lymphocytes. No cytotoxicity was observed for the three antimutagenic agents either.

Adult↗
PubMed1990

Antimutagenic activity of some saponins isolated from Calendula officinalis L., C. arvensis L. and Hedera helix L.

Thirteen saponins were isolated and identified from Calendula officinalis, C. arvensis and Hedera helix. Mutagenic and antimutagenic activities of these products were investigated using a modified liquid incubation technique of the Salmonella/microsomal assay. The Salmonella tester strain TA98 +/- S9 mix was used. Screening of the antimutagenic activity was performed with a known promutagen: benzo-[a]pyrene (BaP) and a mutagenic urine concentrate from a smoker (SU). Antimutagenic activities were also compared with the activity of chlorophyllin. All the saponins were found to be non-toxic and non-mutagenic for doses of 400 micrograms. Chlorophyllin inhibited the mutagenic activities of BaP (1 microgram) and SU (5 microliters) in a dose-dependent manner. The four saponins from C. arvensis and the three saponins from H. helix showed antimutagenic activity against BaP (1 microgram) and SU (5 microliters) with a dose-response relationship. The possible mechanism of the antimutagenic activity of saponins is discussed.

Animals↗