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Biomedical subjects

W K Kaufmann

Publications and source records attributed to W K Kaufmann.

At least 37 records · Page 2Linked to original sources
PubMed1996

Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice.

Transforming growth factor-alpha (TGF alpha), a member of the epidermal growth factor receptor ligand family, has been implicated in the regeneration and transformation of liver. Our recent development of mice that are homozygous for a disrupted TGF alpha gene allowed us to assess the requirement for this growth factor in these complex processes. We report here that although a 70% hepatectomy produced a significant increase in hepatic TGF alpha protein levels in wild-type mice, liver regeneration nevertheless proceeded normally in the absence of the growth factor. The hepatocyte labeling indices determined for homozygous targeted and wild-type mice at 36 and 48 h after hepatectomy were comparable, and the total liver DNA to body weight ratios 8 d after hepatectomy were essentially identical for the two genotypes. These results indicate that TGF alpha, is not necessary for liver regeneration. To test its requirement in liver carcinogenesis, young mice were administered single doses of diethylnitrosamine (DEN) with or without subsequent chronic treatment with the promoting agent phenobarbital (PB). Both wild-type and homozygous mutant male mice treated with DEN or DEN plus PB developed multiple preneoplastic foci or tumors by 9 mo of age with relatively high incidence. However, while five of 88 tumors in wild-type mice attained a diameter greater than 5 mm and were classified as hepatocellular carcinomas, none of 132 tumors in livers of targeted mice reached this size. Furthermore, three of these large wild-type tumors expressed significantly elevated levels of TGF alpha protein compared with normal liver. These results indicate that TGF alpha is not required for early events in chemically induced hepatocarcinogenesis but suggest that it could be important in the progression from small preneoplastic foci to large tumors.

Animals↗
PubMed1996

DNA damage and cell cycle checkpoints.

DNA is prone to numerous forms of damage that can injure cells and impair fitness. Cells have evolved an array of mechanisms to repair these injuries. Proliferating cells are especially vulnerable to DNA damage due to the added demands of cellular growth and division. Cell cycle checkpoints represent integral components of DNA repair that coordinate cooperation between the machinery of the cell cycle and several biochemical pathways that respond to damage and restore DNA structure. By delaying progression through the cell cycle, checkpoints provide more time for repair before the critical phases of DNA replication, when the genome is replicated, and of mitosis, when the genome is segregated. Loss or attenuation of checkpoint function may increase spontaneous and induced gene mutations and chromosomal aberrations by reducing the efficiency of DNA repair. Defects in checkpoint control have been seen in certain hereditary cancer syndromes and at early stages of cell transformation. Mutations in checkpoint control genes therefore may contribute to the genetic instability that appears to drive neoplastic evolution.

Animals↗
PubMed1995

p21CIP1 is not required for the early G2 checkpoint response to ionizing radiation.

We have previously reported that the immediate G2 checkpoint delay of normal human fibroblasts in response to ionizing radiation is correlated with inhibition of p34CDC2/cyclin B kinase activity. Here, we observed increased amounts of the cyclin-dependent protein kinase inhibitor p21CIP1 associated with p34CDC2/cyclin B protein complexes from irradiated normal human fibroblasts. Since wild-type p53 function is not required for the early G2 checkpoint response to ionizing radiation, we investigated whether a p53-independent induction of p21CIP1 was required for the G2 checkpoint. Early passage human fibroblasts expressing the E6 oncoprotein of human papilloma virus-type 16 (NHF4 E6) were analyzed. It has been demonstrated earlier than inactivation of wild-type p53 function in these cells by E6 protein does not alter their intact early G2 checkpoint response to gamma-rays. p21CIP1 was found to be undetectable in p34CDC2/cyclin B protein complexes and in total extracts from the E6-expressing cells, with or without exposure to ionizing radiation. These data indicate that p21CIP1 is not required for the immediate G2 checkpoint response and is not induced by a p53-independent pathway in G2 phase following exposure to gamma-rays.

Cell Cycle↗
PubMed1995

Defective G2 checkpoint function in cells from individuals with familial cancer syndromes.

The early events in the G2 checkpoint response to ionizing radiation (IR) were analyzed in diploid normal human fibroblasts (NHFs) and fibroblasts from patients with two heritable cancer syndromes. Exposure to gamma-radiation of asynchronously growing NHFs resulted in a rapid reduction in the number of cells in mitosis (G2 delay) and was accompanied by a quantitatively similar reduction in the p34CDC2/cyclin B in vitro histone H1 kinase activity as compared with sham-treated controls. This G2 delay was strong by 1 h following exposure to IR, maximal by 2 h, and was accompanied by an accumulation of tyrosine-phosphorylated p34CDC2 molecules. In contrast, fibroblasts from individuals with ataxia telangiectasia displayed significantly less reduction of the mitotic index or histone H1 kinase activity after IR. Low passage fibroblasts from individuals with Li-Fraumeni syndrome having one wild-type and one mutated p53 allele were similar to NHFs in their immediate G2 checkpoint response to IR, as were NHFs expressing the human papilloma virus type 16 E6 gene product (functionally inactivating p53) and low passage cells from p53-deficient mouse embryos. However, the p53-deficient fibroblasts were genomically unstable and became defective in their early G2 checkpoint response to IR. Furthermore, immortal Li-Fraumeni syndrome fibroblasts lacking wild-type p53 displayed an attenuated G2 checkpoint response. These results link the early events in G2 checkpoint response to IR in NHFs with a rapid inhibition of p34CDC2/cyclin B protein kinase activity and demonstrate that while not required for this immediate G2 delay, lack of p53 can lead to subsequent genetic alterations that result in defective G2 checkpoint function.

Ataxia Telangiectasia↗
PubMed1995

Attenuation of G2 checkpoint function precedes human cell immortalization.

We have investigated the hypothesis that attenuation of the G2 checkpoint, which delays entry into mitosis in response to damage to DNA and protects against clastogenesis, may contribute to the genetic instability of immortal human cell lines. IMR-90 normal human fibroblasts displayed stringent G2 checkpoint response to gamma-radiation-induced DNA damage. Irradiation with 1.5 Gy induced 98% inhibition of mitosis and 79% inhibition of cyclin B1/p34CDC2 kinase activity within 2 h. SV40-transformed IMR-90 cells with extended in vitro proliferative lifespan and immortal derivative cells displayed significantly less radiation-induced G2 delay (60-70%) and less inhibition of cyclin B1/p34CDC2 protein kinase activity (43-46%) than was seen in normal cells. Two other SV40-transformed lines and a fibrosarcoma line displayed a similar attenuation of G2 checkpoint function. The attenuation of G2 checkpoint function in SV40 transformed IMR-90 cells was associated with elevated levels of expression of cyclin B1 (8-fold greater) and p34CDC2 (2.5-fold greater). By allowing cells with damaged chromatids to enter mitosis, an attenuation of G2 checkpoint function in finite lifespan cells may promote the genetic alterations necessary for the conversion to immortality.

Cell Cycle↗
PubMed1995

Xeroderma pigmentosum variant: generation and characterization of fibroblastic cell lines transformed with SV40 large T antigen.

Xeroderma pigmentosum variant (XPV) fibroblasts from the XP4BE strain (CRL1162) were transformed with the SV40 large T antigen with the purpose of generating immortalized cell lines that are defective in post-replication repair (PRR). Two transformation and selection protocols were used and at least two independent clones were obtained, which behaved in culture as immortal cell lines. Fingerprinting analyses were used to demonstrate their origin from XP4BE cells and to compare their genetic profiles. These cell lines were shown to be hypersensitive to killing by uv when compared to SV40-transformed fibroblasts derived from foreskins of normal neonates. One of the XPV transformed cell lines (CTag) was characterized further as a potential source of cell-free extracts with capability for catalyzing the T antigen-dependent in vitro replication of plasmid DNA carrying the SV40 origin of replication. In this assay system, CTag extracts were shown to be as active as those produced from HeLa cells. In vitro replication of uv-damaged plasmid DNA by protein extracts from PRR-defective (XPV) and PRR-proficient cells might allow the identification and characterization of protein factors that contribute to normal replication of uv-damaged DNA. Ultraviolet irradiation of plasmid DNA templates caused dose-dependent inhibition of in vitro replication by both HeLa and CTag extracts.

Antigens, Polyomavirus Transforming↗
PubMed1995

Cell cycle checkpoints and DNA repair preserve the stability of the human genome.

Chemical carcinogenesis in the regenerating rat liver is cell-cycle-dependent. Proliferating hepatocytes were maximally susceptible to initiation by a single dose of benzo[a]pyrene diolepoxide I when at the G1/S border. Hepatocytes in early G1 or late S/G2/M were less susceptible and non-proliferating G0 hepatocytes were resistant to initiation. Radiation clastogenesis in proliferating human fibroblasts also is cell-cycle-dependent. Ultraviolet radiation (UV) induced maximal frequencies of chromosomal aberrations in synchronized cells that were at the G1/S border. Cells in early G1 or G2 were significantly less sensitive. For both initiation of chemical carcinogenesis and UV-clastogenesis, it appears that replication of damaged DNA is required and DNA repair before replication reduces cellular risk. If DNA repair is protective, cell cycle checkpoints which delay DNA replication and mitosis should augment this protective influence by providing more time for repair. The contribution of cell cycle checkpoint function to DNA repair during cell cycle-dependent clastogenesis was studied using ataxia telangiectasia (AT) fibroblasts. The AT cells displayed a defect in the coupling of DNA damage to checkpoints which control the G1/S and G2/M transitions and the rate of replicon initiation in S phase cells. UV-clastogenesis in AT cells was cell-cycle-dependent with irradiation at the G1/S boundary inducing 3-times more aberrations than treatment in G0 at the time of release into the cell cycle. Thus, DNA excision repair during the pre-replicative G1 phase was protective even in cells with defective checkpoint function. However, following irradiation at the G1/S border, AT cells displayed about 6-fold increased levels of UV-induced chromosome aberrations in comparison to normal human fibroblasts that were treated at this time. These observations indicate that secondary and tertiary DNA lesions that are produced during replication of UV-damaged DNA (replicative gaps and double-strand breaks) also depend on checkpoint function for repair. The replicon initiation and G2-delay checkpoints that operate after initiation of S phase appear to play a major role in protection against UV-clastogenesis.

Animals↗
PubMed1995

Phenobarbital modulates the type of cell death by rat hepatocytes during deprivation of serum in vitro.

An immortal line of chemically altered rat hepatocytes was used to study the effects of the liver tumor promoter, phenobarbital (PB), on hepatocyte growth and viability in vitro. When the serum concentration in medium was changed from 10% to 0.5%, cell proliferation decreased and hepatocytes died. Death of the hepatocytes occurred after 2 days in low-serum medium. PB appeared to control the type of cell death that occurred. In the absence of PB in low-serum medium, most dead cells had morphological changes that are characteristic of necrosis as determined by both light and electron microscopy. In the presence of PB, the dead cells had alterations typical of apoptosis. Biochemical features of cell death in low-serum medium were also analyzed. DNA isolated from cells in low serum with PB showed nucleosome-length fragments after gel electrophoresis, whereas DNA from cells in low serum without PB appeared as randomly degraded fragments. Although proliferation of hepatocytes in low-serum decreased by 75%, the appearance of apoptosis in the presence of PB was associated with increased expression of the c-myc gene. Based on these observations, we conclude that PB can modulate the type of cell death that occurs after serum deprivation in this line of immortal rat hepatocytes. PB seemed to prevent necrotic cell death in low serum, and cells died through a gene-directed pathway of apoptosis.

Animals↗
PubMed1995

Derivation of phenobarbital-responsive immortal rat hepatocytes.

Two lines of rat hepatocytes, designated 6/15 and 6/27, were obtained from carcinogen-treated livers by cultivation in medium containing the liver tumor promoter, phenobarbital (PB). Both lines appeared to be PB-responsive and to have an unlimited in vitro proliferative lifespan, i.e., immortality. The ability of pure 6/27 hepatocytes to form colonies from single cells was strictly dependent upon PB; it was reduced by 97 to 99% in the absence of PB. These hepatocytes were not tumorigenic. For 6/27 hepatocytes in early passages where cultures contained fibroblast contaminants and later when they were a pure culture, PB was able to enhance colony growth from single cells and facilitated population expansion by sustaining DNA synthesis and by inhibiting cell lysis. The 6/15 line displayed PB-dependent colony formation and was not tumorigenic at early passages. At later passages 6/15 hepatocytes were less dependent on PB for colony formation, and they formed hepatocellular carcinoma when transplanted into livers of syngeneic rats. The demonstration that PB sustained the proliferation and viability of hepatocytes with enhanced growth capacity and indefinite proliferative lifespan suggests that PB may be necessary for progression of these chemically initiated hepatocytes to immortal and tumorigenic lines in vitro.

Animals↗
PubMed1994

Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines.

We have examined the relationship between cis-diamminedichloroplatinum(II) (cisplatin) resistance and replicative bypass in the human ovarian carcinoma cell lines 2008, A2780, and their respective cisplatin-resistant derivatives C13* and A2780/DDP. Replicative bypass is defined as the ability of a replication complex to proceed past a DNA adduct known to block or stall the complex during synthesis. Previous studies in our laboratory have shown a 3-4-fold increase in the replicative bypass of platinum-DNA adducts in platinum-resistant murine leukemia cell lines [G. R. Gibbons et al, Carcinogenesis (Lond.), 12: 2253-2257, 1991]. To test for this effect in the human lines, we used a steady-state replication assay which measures the inhibition of DNA chain elongation (based on the incorporation of [3H]thymidine into nascent DNA strands) as a function of the number of platinum-DNA adducts present on the DNA following cisplatin treatment. With this technique we demonstrated a 4.5-fold increase in the replicative bypass ability of the C13* line compared to the 2008 line and a 2.3-fold increase in the bypass ability of the A2780/DDP line compared to the A2780 line. To confirm these results, we performed a pulse-chase replication assay on the 2008 and C13* lines. This assay differs from the first in that DNA chain elongation is measured in a time-dependent manner. With the pulse-chase assay we observed a 4.8-fold increase in the replicative bypass ability of the C13* line compared to the 2008 line. We then examined the specificity of this enhanced bypass by repeating the steady-state assay with the 2008 and C13* lines using as damaging agents 1,2-diaminocyclohexanedichloroplatinum(II), UV radiation (producing pyrimidine dimers), and benzo(a)pyrene-7,8-diol-9,10-epoxide. In both cell lines, 1,2-diaminocyclohexanedichloroplatinum(II)-DNA adducts caused a greater inhibition of DNA chain elongation than cisplatin-DNA adducts. The level of enhanced bypass of 1,2-diaminocyclohexanedichloroplatinum(II)-DNA adducts in the resistant line was 2.1-fold (approximately 2-fold less than the level of enhanced bypass observed with cisplatin-DNA adducts). There was no evidence of enhanced bypass in the resistant line when cells were treated with UV light or benzo(a)pyrene-7,8-diol-9,10-epoxide. These results indicate that the bypass response in the C13* line has some degree of specificity for cisplatin adducts. The specificity of bypass in these cell lines coincided well with the specificity of resistance to each agent.(ABSTRACT TRUNCATED AT 400 WORDS)

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1994

Retrospective assessment of liver cell proliferation via PCNA: a comparison with tritiated thymidine.

Cell proliferation (S phase response) in archival liver tissues of partially hepatectomized rats was determined via proliferating cell nuclear antigen (PCNA) immunohistochemistry. These results were compared with the S phase response assessed previously in the same tissues via tritiated thymidine (Tdr) autoradiography. The effect of prolonged tissue fixation on PCNA immunohistochemistry was compared in two studies: study A, the liver was fixed for a maximum of 7 days and then embedded in paraffin and stored for approximately 18 months, while in study B, the liver was fixed in formalin for 7 years and then embedded in paraffin and stored for approximately 18 months until sectioning and immunostaining. PCNA immunostaining was successful in the liver sections of both studies, irrespective of the length of formalin fixation. Furthermore, the S phase labeling indices (LI) determined via PCNA and Tdr were comparable, although not identical, in the two studies. Therefore, use of PCNA immunohistochemistry should allow retrospective staining of rodent tissues for the assessment of cell proliferative activity in formalin-fixed organs from previously conducted toxicity and carcinogenicity studies.

Animals↗
PubMed1994

p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest.

gamma-Irradiation of human diploid fibroblasts in the G1 interval caused arrest of the cell cycle prior to S phase. This cell cycle block was correlated with a lack of activation of both cyclin E-Cyclin-dependent kinase 2 (Cdk2) and cyclin A-Cdk2 kinases and depended on wild-type p53. Although the accumulation of cyclin A was strongly inhibited in gamma-irradiated cells, cyclin E accumulated and bound Cdk2 at normal levels but remained in an inactive state. We found that both whole-cell lysates and inactive cyclin E-Cdk2 complexes prepared from irradiated cells contained an activity capable of inactivating cyclin E-Cdk2 complexes. The protein responsible for this activity was shown to be p21CIP1/WAF1, recently described as a p53-inducible Cdk inhibitor. Our data suggest a model in which ionizing radiation confers G1 arrest via the p53-mediated induction of a Cdk inhibitor protein.

Base Sequence↗
PubMed1994

G1 arrest and cell-cycle-dependent clastogenesis in UV-irradiated human fibroblasts.

The demonstrations of frequent allelic deletions in lung and colon cancers have reemphasized the importance of clastogenesis in carcinogenesis. We have investigated the mechanisms of induction of chromosome aberrations in ultraviolet-irradiated diploid human fibroblasts. Cells were irradiated with UV at various times during a parasynchronous wave of cell proliferation and then harvested during the first mitosis that followed irradiation. Metaphase spreads were stained with Geimsa and the yields of chromosome aberrations were quantified. Ultraviolet irradiation induced primarily chromatid-type chromosome aberrations which included chromatid breaks and exchanges. Frequencies of aberrations displayed significant differences according to the phase of the cell cycle in which irradiation occurred and the time after irradiation when metaphases were harvested. Fibroblasts that were irradiated when in G0 and then immediately replated to stimulate cell division and cells that were at the S/G2 border when irradiated displayed the fewest numbers of aberrations. For G0-irradiated cells, the first entering mitosis carried a higher frequency of aberrations than those collected 2-4 h later. In contrast, for S/G2-irradiated cells the first into mitosis displayed fewer aberrations than subsequent fractions. Cells that were irradiated when at the G1/S border displayed the greatest numbers of aberrations with the frequencies of chromatic exchanges being significantly increased over all other times of irradiation. These studies confirm that UV is an S-phase-dependent clastogen and point to the G1/S border as a time of maximal sensitivity to clastogenesis. Irradiation of G1 cells was shown to produce a fluence-dependent reduction in the rate of entry of cells into the S-phase. There appeared to be a point late in G1 beyond which cells were resistant to irradiation and experienced less delay in S phase entry. Ataxia telangiectasia fibroblasts failed to delay entry to S phase following UV-irradiation in G1 and displayed hypersensitivity to UV-induced chromosomal aberrations. The delay in entry of damaged cells into the S phase may have the beneficial effect of providing more time for repair of potentially clastogenic DNA damage before the onset of DNA replication.

Ataxia Telangiectasia↗
PubMed1993

Cell cycle control, DNA repair and initiation of carcinogenesis.

We hypothesize that degradation of controls that normally act to inhibit cell proliferation is an early step in carcinogenesis. This alteration gives rise to initiated clones that display a selective growth advantage over normal cells when subjected to appropriate growth-promoting influences. In cell culture, such initiated cells also may display a selective growth advantage that lets them proliferate under conditions in which normal cell growth ceases. Cells with these properties have been designated enhanced-growth variants (EGVs)2 (1) or extended life span variants (ELVs) (2). We propose that the EGV/ELV phenotypes in vitro and initiation of carcinogenesis in vivo are consequences of genetic changes in pathways that regulate the passage of cells through the cell cycle. These regulatory pathways normally delay or arrest cell cycle progression in response to homeostatic regulators and DNA damage. DNA damage induced by a variety of genotoxic agents triggers delays in cycle progression at three steps of the cell cycle. Two of these involve delays in progression from G1 into S phase and G2 into mitosis. The third occurs within S phase cells and involves reduction in the rate of initiation of DNA synthesis in replicon clusters. If these cycle delay responses fail, damaged DNA may be replicated before it is adequately repaired. This would enhance production of additional genetic alterations. Thus, mutations in genes that normally exert a negative control over cell cycle progression may give cells a growth advantage and make the cells more genetically unstable.

Animals↗
PubMed1992

Initiation by bleomycin of hepatocellular foci in the rat.

The antitumor antibiotic, bleomycin, was tested for activity as an initiator of hepatocellular foci and neoplasms in rats. The compound was administered in a single dose via the portal vein 4 h after the proliferative stimulus of a two-thirds partial hepatectomy. Rats were subsequently fed diet containing phenobarbital for up to 41 weeks to promote the development of initiated hepatocytes. Bleomycin-treated livers displayed significantly increased frequencies of basophilic hepatocellular foci and hepatocellular foci which retain glycogen during fasting. Foci that express glutathione-S-transferase (placental form) were not initiated by bleomycin. Hepatocellular neoplasms were infrequently seen in bleomycin-treated livers (5% incidence). The results suggest that oxygen radical-mediated DNA damage may initiate, within populations of proliferating hepatocytes, new lineages of altered hepatocytes that form foci but have low probability of progressing to neoplasms during promotion with phenobarbital.

Animals↗
PubMed1992

Association between expression of transforming growth factor-alpha and progression of hepatocellular foci to neoplasms.

Hepatocarcinogenesis was initiated in rats with a single dose of either of two chemical mutagens--benzo[a]pyrene diolepoxide I and methyl(acetoxymethyl)nitrosamine--administered 15 h after partial hepatectomy. The development of hepatocellular foci and neoplasms was then promoted with dietary phenobarbital given for 45 or 62 weeks. Formalin-fixed tissue specimens that contained hepatic neoplasms and altered hepatocellular foci were screened for expression of the oncodevelopmental marker glutathione-S-transferase (placental form) (GSTP) and transforming growth factor-alpha (TGF-alpha) using immunohistochemistry. All (100%) hepatocellular carcinomas expressed both GSTP and TGF-alpha, as did most hepatocellular adenomas (greater than 80%). However, quantitative stereologic analysis of treated and control livers revealed that GSTP-positive foci were 10-30 times more frequent than TGF-alpha-positive foci. Foci with homogeneous expression of GSTP generally displayed heterogeneous expression of TGF-alpha with reaction product most prominent at their peripheries. Less frequently homogeneous TGF-alpha-positive foci were seen within GSTP-positive foci. The average volumes of those GSTP-positive foci that also expressed TGF-alpha were significantly greater than those of the entire sets of GSTP-positive foci. These results suggest that expression of TGF-alpha may distinguish a subset of GSTP-positive foci that have a growth advantage and increased probability of progression to neoplasia.

Adenoma↗
PubMed1991

Role of postreplication repair in transformation of human fibroblasts to anchorage independence.

Cellular capacity for postreplication repair (PRR) and sensitivity to transformation to anchorage independence (AI) were quantified in normal foreskin and xeroderma pigmentosum (XP) variant fibroblasts after treatment with UV or benzo(a)pyrene-diol-epoxide I (BPDE-I). PRR is defined here as a collection of pathways that facilitate the replication of DNA damaged by genotoxic agents. It is recognized biochemically as the process by which nascent DNA grows longer than the average distance between two lesions in the DNA template. PRR refers more directly to the elimination of gaps in the daughter-strand DNA by mechanisms which remain to be determined for human cells, but which may include translesion replication and recombination. PRR was measured in diploid human fibroblasts by analysis of the dose kinetics for inhibition of DNA strand growth in carcinogen-treated cells. Logarithmically growing foreskin fibroblasts (NHF1) displayed D0 values of 4.3 J/m2 and 0.14 microM for the inhibition of DNA synthesis in active replicons by UV and BPDE-I, respectively. XP variant cells (CRL1162) exhibited corresponding D0 values of 1.5 J/m2 and 0.16 microM. The increased sensitivity to inhibition of DNA replication by UV in these XP variant fibroblasts (2.9-fold greater than normal) was mirrored by an enhanced frequency of transformation to AI. XP variant fibroblasts (CRL1162) were 3.2 times more sensitive to transformation to AI by UV than were the normal foreskin fibroblasts. As predicted by the PRR studies, both cell types exhibited similar frequencies of AI colonies induced by BPDE-I. Apparent thresholds were observed for induction of AI by UV (normal fibroblasts, 2.7 J/m2; XP variant fibroblasts, 0.3 J/m2) and BPDE-I (both, 0.05 microM). Doses of UV and BPDE-I above these thresholds produced proportional increases in the inhibition of DNA replication in operating replicons and in the induced frequency of anchorage-independent colonies. At doses of UV and BPDE-I that produced the same degree of inhibition of DNA strand growth, BPDE-I induced a greater number of cells capable of anchorage-independent growth than did UV in both normal and XP variant fibroblasts.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗