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A Vaisman

Publications and source records attributed to A Vaisman.

At least 19 recordsLinked to original sources
PubMed2001

Unique misinsertion specificity of poliota may decrease the mutagenic potential of deaminated cytosines.

DNA polymerase iota (poliota) is a distributive error-prone enzyme that can incorporate nucleotides opposite a variety of DNA lesions. Further elongation is, however, either substantially inhibited or completely abolished. Here, we provide evidence that poliota can facilitate the efficient bypass of uracil and its derivatives as well as oxidized cytosine and guanine residues. The fidelity of translesion replication depends upon the lesion encountered. Correct nucleotides were inserted preferentially opposite 7,8-dihydro-8-oxoguanine (8-oxoG) and 5-hydroxycytosine (5-OHC). However, when bypassing uracil, 5-hydroxyuracil (5-OHU) or 5,6-dihydrouracil (5,6-DHU), poliota inserted T and G with a 4- to 26-fold preference over the Watson-Crick base, A. While the T:U, T:5-OHU and T:5,6-DHU mispairs were extended poorly, the G:U, G:5-OHU and G:5,6-DHU mispairs were extended with equal or greater efficiency than the correctly paired primer termini. Thus, poliota-dependent misinsertion of G opposite uracil and its derivatives may actually provide a mechanism whereby mammalian cells can decrease the mutagenic potential of lesions formed via the deamination of cytosine.

Animals↗
PubMed2001

Human DNA polymerase iota promiscuous mismatch extension.

Human DNA polymerase iota is a low-fidelity template copier that preferentially catalyzes the incorporation of the wobble base G, rather than the Watson-Crick base A, opposite template T (Tissier, A., McDonald, J. P., Frank, E. G., and Woodgate, R. (2000) Genes Dev. 14, 1642-1650; Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S., and Prakash, L. (2000) Nature 406, 1015-1019; Zhang, Y., Yuan, F., Wu, X., and Wang, Z. (2000) Mol. Cell. Biol. 20, 7099-7108). Here, we report on its ability to extend all 12 possible mispairs and 4 correct pairs in different sequence contexts. Extension from both matched and mismatched primer termini is generally most efficient and accurate when A is the next template base. In contrast, extension occurs less efficiently and accurately when T is the target template base. A striking exception occurs during extension of a G:T mispair, where the enzyme switches specificity, "preferring" to make a correct A:T base pair immediately downstream from an originally favored G:T mispair. Polymerase iota generates a variety of single and tandem mispairs with high frequency, implying that it may act as a strong mutator when copying undamaged DNA templates in vivo. Even so, its limited ability to catalyze extension from a relatively stable primer/template containing a "buried" mismatch suggests that polymerase iota-catalyzed errors are confined to short template regions.

Base Pair Mismatch↗
PubMed2001

The effect of DNA structure on the catalytic efficiency and fidelity of human DNA polymerase beta on templates with platinum-DNA adducts.

DNA adducts formed by platinum-based anticancer drugs interfere with DNA replication. The carrier ligand of the platinum compound is likely to affect the conformation of the Pt-DNA adducts. In addition, the conformation of the adduct can also change upon binding of damaged DNA to the active site of DNA polymerase. From the crystal structures of pol beta ternary complexes it is evident that undamaged gapped and primed single-stranded (non-gapped) DNA templates exist in very different conformations when bound to pol beta. Therefore, one might expect that the constraints imposed on the damaged templates by binding to the polymerase active site should also affect the conformation of the Pt-DNA adducts and their ability to inhibit DNA replication. In support of this hypothesis we have found that the efficiency, carrier ligand specificity, site of discrimination (3'-G versus 5'-G of the Pt-GG adducts), and fidelity of translesion synthesis past Pt-DNA adducts by pol beta are strongly affected by the structure of the DNA template. Previous studies have suggested that the conformation of Pt-DNA adducts may be affected by the sequence context of the adduct. In support of this hypothesis, our data show that sequence context affects the efficiency, fidelity, and pattern of misincorporation by pol beta.

Antineoplastic Agents↗
PubMed2001

Biochemical characterization of human DNA polymerase iota provides clues to its biological function.

The human RAD30B gene has recently been shown to encode a novel DNA polymerase, DNA polymerase iota (poliota). The role of poliota within the cell is presently unknown, and the only clues to its cellular function come from its biochemical characterization in vitro. The aim of this short review is, therefore, to summarize the known enzymic activities of poliota and to speculate as to how these biochemical properties might relate to its in vivo function.

Base Pair Mismatch↗
PubMed2000

The efficiency and fidelity of translesion synthesis past cisplatin and oxaliplatin GpG adducts by human DNA polymerase beta.

DNA polymerase beta (pol beta) is the only mammalian DNA polymerase identified to date that can catalyze extensive bypass of platinum-DNA adducts in vitro. Previous studies suggest that DNA synthesis by pol beta is distributive on primed single-stranded DNA and processive on gapped DNA. The data presented in this paper provide an analysis of translesion synthesis past cisplatin- and oxaliplatin-DNA adducts by pol beta functioning in both distributive and processive modes using primer extension and steady-state kinetic experiments. Translesion synthesis past Pt-DNA adducts was greater with gapped DNA templates than with single-stranded DNA templates. In the processive mode pol beta did not discriminate between cisplatin and oxaliplatin adducts, while in the distributive mode it displayed about 2-fold increased ability for translesion synthesis past oxaliplatin compared with cisplatin adducts. The differentiation between cisplatin and oxaliplatin adducts resulted from a K(m)-mediated increase in the efficiency of dCTP incorporation across from the 3'-G of oxaliplatin-GG adducts. Rates of misincorporation across platinated guanines determined by the steady-state kinetic assay were higher in reactions with primed single-stranded templates than with gapped DNA and a slight increase in the misincorporation of dTTP across from the 3'-G was found for oxaliplatin compared with cisplatin adducts.

Antineoplastic Agents↗
PubMed2000

Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase eta.

Platinum anticancer agents form bulky DNA adducts which are thought to exert their cytotoxic effect by blocking DNA replication. Translesion synthesis, one of the pathways of postreplication repair, is thought to account for some resistance to DNA damage and much of the mutagenicity of bulky DNA adducts in dividing cells. Oxaliplatin has been shown to be effective in cisplatin-resistant cell lines and less mutagenic than cisplatin in the Ames assay. We have shown that the eukaryotic DNA polymerases yeast pol zeta, human pol beta, and human pol gamma bypass oxaliplatin-GG adducts more efficiently than cisplatin-GG adducts. Human pol eta, a product of the XPV gene, has been shown to catalyze efficient translesion synthesis past cis, syn-cyclobutane pyrimidine dimers. In the present study we compared translesion synthesis past different Pt-GG adducts by human pol eta. Our data show that, similar to other eukaryotic DNA polymerases, pol eta bypasses oxaliplatin-GG adducts more efficiently than cisplatin-GG adducts. However, pol eta-catalyzed translesion replication past Pt-DNA adducts was more efficient and less accurate than that seen for previously tested polymerases. We show that the efficiency and fidelity of translesion replication past Pt-DNA adducts appear to be determined by both the structure of the adduct and the DNA polymerase active site.

Base Sequence↗
PubMed2000

Oxaliplatin-induced damage of cellular DNA.

Damage to cellular DNA is believed to determine the antiproliferative properties of platinum (Pt) drugs. This study characterized DNA damage by oxaliplatin, a diaminocyclohexane Pt drug with clinical antitumor activity. Compared with cisplatin, oxaliplatin formed significantly fewer Pt-DNA adducts (e.g., 0.86+/-0.04 versus 1.36+/- 0.01 adducts/10(6) base pairs/10 microM drug/1 h, respectively, in CEM cells, P<.01). Oxaliplatin was found to induce potentially lethal bifunctional lesions, such as interstrand DNA cross-links (ISC) and DNA-protein cross-links (DPC) in CEM cells. As with total adducts, however, oxaliplatin produced fewer (P<.05) bifunctional lesions than did cisplatin: 0.7+/-0.2 and 1.8+/-0.3 ISC and 0.8+/-0.1 and 1.5+/-0.3 DPC/10(6) base pairs/10 microM drug, respectively, after a 4-h treatment. Extended postincubation (up to 12 h) did not compensate the lower DPC and ISC levels by oxaliplatin. ISC and DPC determinations in isolated CEM nuclei unequivocally verified that oxaliplatin is inherently less able than cisplatin to form these lesions. Reactivation of drug-treated plasmids, observed in four cell lines, suggests that oxaliplatin adducts are repaired with similar kinetics as cisplatin adducts. Oxaliplatin, however, was more efficient than cisplatin per equal number of DNA adducts in inhibiting DNA chain elongation ( approximately 7-fold in CEM cells). Despite lower DNA reactivity, oxaliplatin exhibited similar or greater cytotoxicity in several other human tumor cell lines (50% growth inhibition in CEM cells at 1.1/1.2 microM, respectively). The results demonstrate that oxaliplatin-induced DNA lesions, including ISC and DPC, are likely to contribute to the drug's biological properties. However, oxaliplatin requires fewer DNA lesions than does cisplatin to achieve cell growth inhibition.

Antineoplastic Agents↗
PubMed1999

Effect of DNA polymerases and high mobility group protein 1 on the carrier ligand specificity for translesion synthesis past platinum-DNA adducts.

Translesion synthesis past Pt-DNA adducts can affect both the cytotoxicity and mutagenicity of the platinum adducts. We have shown previously that the extent of replicative bypass in vivo is influenced by the carrier ligand of platinum adducts. The specificity of replicative bypass may be determined by the DNA polymerase complexes that catalyze translesion synthesis past Pt-DNA adducts and/or by DNA damage-recognition proteins that bind to the Pt-DNA adducts and block translesion replication. In the present study, primer extension on DNA templates containing site-specifically placed cisplatin, oxaliplatin, JM216, or chlorodiethylenetriamine-Pt adducts revealed that the eukaryotic DNA polymerases beta, zeta, gamma, and human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) had a similar specificity for translesion synthesis past Pt-DNA adducts (dien >> oxaliplatin >/= cisplatin > JM216). Primer extension assays performed in the presence of high mobility group protein 1 (HMG1), which is known to recognize cisplatin-damaged DNA, revealed that inhibition of translesion synthesis by HMG1 also depended on the carrier ligand of the Pt-DNA adduct (cisplatin > oxaliplatin = JM216 >> dien). These data were consistent with the results of gel-shift experiments showing similar differences in the affinity of HMG1 for DNA modified with the different platinum adducts. Our studies show that both DNA polymerases and damage-recognition proteins can impart specificity to replicative bypass of Pt-DNA adducts. This information may serve as a model for further studies of translesion synthesis.

Base Sequence↗
PubMed1999

Efficient nucleotide excision repair of cisplatin, oxaliplatin, and Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts.

Tumors exhibit a spectrum of cellular responses to chemotherapy ranging from extreme sensitivity to resistance, either intrinsic or acquired. These variable responses are both patient and tumor specific. For platinum DNA-damaging agents, drug resistance depends on the carrier ligand of the platinum complex and is due to a combination of mechanisms including DNA repair. Nucleotide excision repair is the only known mechanism by which bulky adducts, including those generated by platinum chemotherapeutic agents, are removed from DNA in human cells. In this report, we show that the types of DNA lesions generated by three platinum drugs, cisplatin, oxaliplatin, and (Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216), are repaired in vitro with similar kinetics by the mammalian nucleotide excision repair pathway.

Animals↗
PubMed1999

Specificity of platinum-DNA adduct repair.

Cell lines with resistance to cisplatin and carboplatin often retain sensitivity to platinum complexes with different carrier ligands (e.g., oxaliplatin and JM216). HeLa cell extracts were shown to excise cisplatin, oxaliplatin, and JM216 adducts with equal efficiency, suggesting that nucleotide excision repair does not contribute to the carrier-ligand specificity of platinum resistance. We have shown previously that the extent of replicative bypass in vivo is influenced by the carrier ligand of the platinum adducts. The specificity of replicative bypass may be determined by the DNA polymerase complexes that catalyze translesion synthesis past Pt-DNA adducts, by the mismatch-repair system that removes newly synthesized DNA opposite Pt-DNA adducts, and/or by DNA damage-recognition proteins that bind to the Pt-DNA adducts and block translesion synthesis. Primer extension on DNA templates containing site-specifically placed cisplatin, oxaliplatin, or JM216 Pt-GG adducts revealed that the eukaryotic DNA polymerases beta, zeta, gamma and HIV-1 RT had a similar specificity for translesion synthesis past Pt-DNA adducts (oxaliplatin > or = cisplatin > JM216). In addition, defects in the mismatch-repair proteins hMSH6 and hMLH1 led to increased replicative bypass of cisplatin adducts, but not of oxaliplatin adducts. Finally, primer extension assays performed in the presence of HMG1, which is known to recognize cisplatin-damaged DNA, revealed that inhibition of translesion synthesis by HMG1 also depended on the carrier ligand of the Pt-DNA adduct (cisplatin > oxaliplatin = JM216). These studies show that DNA polymerases, the mismatch-repair system and damage-recognition proteins can all impart specificity to replicative bypass of Pt-DNA adducts. Replicative bypass, in turn, may influence the carrier-ligand specificity of resistance.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts.

Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts. Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found. Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts. These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Cell cycle changes associated with formation of Pt-DNA adducts in human ovarian carcinoma cells with different cisplatin sensitivity.

The possible correlation between alterations in cytokinetic response to cisplatin (CP) treatment and drug resistance in human ovarian carcinoma cell lines was examined. Using dual parameter flow cytometry, we performed detailed time-course and dose-response analysis of cell cycle modifications in the parental A2780 and resistant A2780/CP cells exposed to CP. The data suggested that drug treatment resulted in similar types of cell cycle alterations in cells with different CP sensitivity. Rapid normalization of the cytokinetic pattern in both cell lines at low doses of CP was observed. At higher drug concentrations reversible S phase delay predominated, accompanied by blocks in both G1/S and G2/M and followed by complete normalization of cytokinetic patterns in the surviving cells. CP treatment by lethal doses resulted in almost complete S phase block. The surviving cells at 72 h accumulated in G2 phase. CP-induced cell cycle perturbations, among which the most pronounced were alterations in the S phase populations, correlated with the level of DNA damage, but not with cell survival in these cell lines. However, at identical levels of DNA damage, the resistant A2780/CP cell line demonstrated decreased p53 induction and decreased apoptosis compared to the parental cell line. Thus, at equivalent levels of DNA damage, resistance in this model system correlated with a diminished p53-dependent apoptotic pathway rather than with differences in cell cycle response.

Carcinoma↗
PubMed1997

DNA damage inducible-gene expression following platinum treatment in human ovarian carcinoma cell lines.

PURPOSE: DNA damage-inducible genes, such as gadd153, gadd45, p21 and c-jun, have previously been shown to be induced by the chemotherapeutic agent cisplatin. One of these genes, gadd153, has previously been reported to be differentially expressed in cisplatin-resistant cell lines and, therefore, to be a potential prognostic indicator for tumor response to cisplatin-based chemotherapy. It is not currently known whether such damage-inducible genes are turned on by the DNA damage itself (e.g. by the formation of Pt-DNA adducts) or by the downstream biological consequences of that damage. It is also not known whether the increased expression of these DNA-damage-inducible genes is related to immediate protective responses such as DNA repair or to more delayed responses such as cell cycle arrest or apoptosis. These experiments were initiated to characterize more fully the nature of the DNA damage-inducible response to cisplatin treatment and to determine whether any of these genes might be useful prognostic indicators of tumor response to cisplatin chemotherapy. METHODS: The dose-response and time-course for the induction of the DNA damage-inducible genes gadd153, gadd45, p21 and c-jun were examined by Northern analysis in the human ovarian carcinoma cell line 2008 and its resistant subclone C13* following treatment with platinum anticancer agents. The extent of gene expression was correlated with cytotoxicity determined by growth inhibition assay, Pt-DNA adducts determined by atomic absorption spectrometry and inhibition of DNA synthesis determined by 3H-thymidine incorporation. RESULTS: All four genes were induced maximally in both sensitive and resistant cell lines at lethal cisplatin doses (> or = ID90). Induction was maximal between 24 and 48 h following exposure to the drug for all genes except c-jun which was induced by 6 h. At 24 h following cisplatin treatment the overall levels of gadd153 were less in the resistant C13* cell line than in the parental 2008 cell line, while those of gadd45 were greater in C13* than in 2008. Maximal expression of p21 and c-jun was not significantly different in the two cell lines. The dose-response of these genes correlated with the cytotoxicity of cisplatin and the inhibition of DNA synthesis by cisplatin, rather than to the actual levels of Pt-DNA adducts. The more cytotoxic platinum analog, ormaplatin, also induced gadd153 and its induction was also based on cytotoxicity. CONCLUSION: These results suggest that the regulation of gadd153 and gadd45 expression occurs thorough separate pathways in the 2008 and C13* cell lines. The DNA damage-inducible gene response for all four damage-inducible genes tested appeared to be more directly correlated with downstream biologic effects of cisplatin damage than with actual Pt-DNA adduct levels. The time-course and dose-response for induction of these genes was more consistent with delayed responses such as apoptosis rather than more immediate responses such as DNA repair. Finally, these results strengthen previous suggestions that the expression of gadd153, and possibly other DNA damage-inducible genes, may be useful indicators of tumor response to cisplatin-based chemotherapy.

Antineoplastic Agents↗
PubMed1996

Cisplatin-induced alterations in the expression of the mRNAs for UV-damage recognition protein.

Enhanced DNA repair is believed to be an important mechanism of the cisplatin-resistant phenotype. UV-damage recognition protein (UV-DRP) recognizes and binds to DNA lesions and may play a role in DNA nucleotide excision repair and/or replicative bypass (which is associated with post-replication repair). Potential alternations in the expression of mRNAs for UV-DRP were analyzed in this study. Two pairs of parental and cisplatin-resistant human ovarian carcinoma cell lines were utilized. Gene expression level was assessed by northern blot hybridization. No alterations in mRNA levels for the large subunit of UV-DRP were found following cisplatin treatment, whereas mRNA levels for the small subunit of UV-DRP were induced up to 4.5-fold. The time-course and concentration-response of this induction corresponded to the previously reported increase in the UV-DRP binding activity, as measured by gel shift assay. UV-DRP binding activity in cell extracts corresponds to expression of small subunit mRNA but not to expression of large subunit mRNA. These data suggest that the small subunit may be limiting for UV-DRP activity.

Antineoplastic Agents↗
PubMed1995

Induction of UV-damage recognition protein by cisplatin treatment.

The biological functions of DNA damage recognition proteins are not well understood. Using the band shift assay, we detected in nuclear extracts from human carcinoma cell lines damage recognition protein which bound selectively to UV-damaged double-stranded DNA. No consistent correlation was found between steady-state levels of the UV-damage recognition protein and either cisplatin cytotoxicity or DNA repair activity. However, cisplatin treatment caused accumulation of the UV-damage recognition protein. The cisplatin-responsive induction of UV-damage recognition protein in the nucleus was higher in cisplatin-resistant cell lines than in their parental counterparts. These results imply that the level of inducibility in response to treatment, but not the constitutive binding activity, of UV-damage recognition protein correlates with cisplatin resistance. Inhibition of UV-damage recognition protein expression by actinomycin and cycloheximide suggests that induction of UV-damage recognition protein requires de novo RNA and protein synthesis, rather than post-translational modification of pre-existing protein. The increased level of UV-damage recognition protein after cisplatin treatment could be a direct response to adduct formation, since it correlated with the number of Pt-DNA adducts. However, it could also be a secondary effect of DNA replication inhibition following DNA damage, since inhibition of DNA synthesis by aphidicolin and hydroxyurea caused the same induction of UV-damage recognition protein. Inducibility of UV-damage recognition protein binding activity by Pt drug treatment suggests involvement of this protein in drug resistance, although a direct link between its function and DNA repair or damage tolerance has not been demonstrated.

Cell Cycle↗
PubMed1995

Organ-specific biotransformation of ormaplatin in the Fischer 344 rat.

We examined the intracellular biotransformation products of ormaplatin [(d,l-trans)1,2-diaminocyclohexanetetrachloroplatinum(IV)] (formerly called tetraplatin) in liver, kidney, spleen, small intestine, and plasma of the adult male Fischer 344 rat. Previous studies have established that the rank order of ormaplatin toxicity in Fischer 344 rats is spleen approximately gastrointestinal tract > kidney >> liver. Animals were given tritium-labelled drug i.v. at 12.5 mg/kg, and tissues were harvested 30 min later. The kidney was found to concentrate total and cytosolic platinum to a greater extent than any of the other tissues. The absolute amount of cytosolic platinum, in micrograms per gram tissue, that was irreversibly bound to protein and/or other macromolecules was also greatest in the kidney. However, when the amount bound was expressed as a percentage of the total cytosolic platinum, the kidney was significantly lower than any other tissue. Of the various low molecular mass platinum biotransformation species characterized, by far the most abundant were complexes of platinum with the sulfur-containing molecules cysteine, methionine, and glutathione (GSH). There was more of the methionine complex in the blood plasma than in any of the tissues except for the spleen. No significant differences among the tissues were detected for the dichloro, cysteine, methionine, or the GSH complexes. The tritium-labelled diaminocyclohexane (DACH) carrier ligand appeared to remain stably bound to the platinum while in the plasma, as there was less free DACH ligand detected in plasma ultrafiltrate than in any tissue ultrafiltrate. Among the tissues, the free DACH levels were in the range of 20% of the radioactivity recovered from the HPLC column and were not significantly different. Consequently, neither biodistribution nor tissue-specific biotransformation of ormaplatin provides a ready explanation for the tissue specificity of ormaplatin toxicity in Fischer 344 rats. However, in kidney there was much less of the reactive PtCl2(DACH) species than has previously been reported for the corresponding Pt(NH3)2Cl2 species in cisplatin-treated rats. Thus, these data suggest a possible explanation for differences in nephrotoxicity induced by cisplatin versus that by ormaplatin.

Analysis of Variance↗
PubMed1995

A clinical and pharmacokinetic study of high-dose carboplatin, paclitaxel, granulocyte colony-stimulating factor, and peripheral blood stem cells in patients with unresectable or metastatic cancer.

We have developed a regimen incorporating multiple cycles of high-dose carboplatin and fixed-dose paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with granulocyte colony-stimulating factor and peripheral blood stem cell support given every 21 days for up to four cycles. Our phase I study of this regimen has treated 26 patients with good performance status and histologically documented unresectable or metastatic carcinoma, sarcoma, or melanoma, 21 of whom received all planned courses every 21 days. Paclitaxel 250 mg/m2 was infused over 24 hours, followed by a 1-hour carboplatin infusion, with doses escalated between area under the concentration-time curve (AUC) targets of 8 and 20. Considering the carboplatin doses administered (two to three times those generally achieved with growth factor support), toxicity has been relatively modest. The median duration of grade 4 neutropenia and thrombocytopenia was not significantly different between the AUCs of 8 and 18, which proved to be the maximum tolerated carboplatin dose. Twelve courses were associated with hospitalization for neutropenic fever or catheter-related thrombophlebitis. One treatment-related death occurred, and severe toxicity caused withdrawal of two patients treated at the AUC of 20. Peripheral neuropathy was the most common serious nonhematologic complication. Pharmacokinetic analysis showed significantly lower measured versus predicted AUC values. Among 25 evaluable patients, preliminary results show one complete response (ovarian cancer) and 11 partial responses, including four in patients with non-small cell lung cancer. Additional issues to be addressed include the effect of a shorter (or longer) paclitaxel infusion on the carboplatin AUC (and the incidence of toxicity) and whether the discrepancy between actual and predicted AUCs (greater in our study than reported elsewhere) is due to the variability of creatinine clearance-determined glomerular filtration rate or to altered carboplatin pharmacokinetics when a short high-dose infusion follows paclitaxel. Additional patients are being accrued at the AUC of 18.

Adult↗