Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

At least 73 records · Page 4Linked to original sources

PubMed1997

all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells.

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index >0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells.

Adenocarcinoma↗

PubMed1997

Pharmacological basis for a novel therapeutic strategy based on the use of aquated cisplatin.

In pursuit of a strategy for increasing delivery of platinum drugs to tumors, we compared the cytotoxicity, extent of cellular uptake, and DNA platination of native cisplatin (DDP) and aquated cisplatin (aqDDP) in human head and neck carcinoma UMSCC10b cells. AqDDP was 1. 8-fold more toxic than DDP when tested against UMSCC10b cells in vitro. At high concentrations, aqDDP uptake was 3-fold more rapid than that of DDP; uptake of DDP and aqDDP was nonsaturable up to a concentration of 1600 micrometer. AqDDP produced 6.4-fold more platination of DNA than did DDP at the same concentration, suggesting that once inside the cell, aqDDP was 2-fold more effective at producing adducts in DNA than the native drug. Despite the paradox that aqDDP, which contains some charged species, entered the cell more rapidly than did neutral native DDP at high concentrations, studies on the effect of temperature, ATP depletion, and sulfhydryl group blockade did not provide evidence for uptake of aqDDP via a channel or transporter. AqDDP was more nephrotoxic to mice than DDP; however, s.c. administration of sodium thiosulfate protected against this toxicity and permitted a 7-fold escalation of aqDDP dose. These studies provide the preclinical basis for a novel therapeutic strategy based on the regional intraarterial or intracavitary administration of aqDDP in combination with a systemic neutralizing agent.

Adenosine Triphosphate↗

PubMed1997

In vitro antineoplastic activity of a novel lanthionine-containing peptide.

It has been a long-term goal to discover peptides that can kill tumor cells while sparing normal tissues. Lan-7 is a novel, chemically stable peptide structurally related to somatostatin that contains a lanthionine bridge between the two cysteines in the peptide; TT-232 is a less stable analogue containing a disulfide bridge. The antitumor activity of Lan-7 was examined, relative to that of TT-232 and the clinically used analogue octreotide, against a panel of malignant human tumor cell lines and normal human hematopoietic precursors. Lan-7 was cytotoxic to all four tumor cell lines, with IC50 values ranging over a 2-fold range from 16 to 36 microM. The potency of Lan-7 was comparable to that of TT-232, and both of these agents were two to three times more potent than octreotide. At concentrations that were highly cytotoxic to tumor cells, Lan-7 produced no significant toxicity to normal human hematopoietic precursors. Lan-7 induced apoptosis in human ovarian carcinoma 2008 cells over the same concentration range at which it produced cytotoxicity, but it did so without activating G1, S, or G2 checkpoints, given that it produced no perturbation of cell cycle phase distribution. Cells engineered to overexpress P-glycoprotein were not more resistant to Lan-7 than isogeneic cells not expressing the mdr1 gene. These results make Lan-7 of interest as a potential cancer chemotherapeutic agent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

The role of DNA mismatch repair in platinum drug resistance.

Loss of DNA mismatch repair occurs in many types of tumors. The effect of the loss of DNA mismatch repair activity on sensitivity to cisplatin and a panel of analogues was tested using two pairs of cell lines proficient or deficient in this function. HCT116+ch2, a human colon cancer cell line deficient in hMLH1, was 2.1-fold resistant to cisplatin and 1.3-fold resistant to carboplatin when compared to a subline complemented with chromosome 3 expressing a wild-type copy of hMLH1. Likewise, the human endometrial cancer cell line HEC59, which is deficient in hMSH2, was 1.8-fold resistant to cisplatin and 1.5-fold resistant to carboplatin when compared to a subline complemented with chromosome 2 with a wild-type hMSH2. In contrast to cisplatin and carboplatin, which form the same types of adducts in DNA, there was no difference in sensitivity between the DNA mismatch repair-proficient and -deficient cell lines for oxaliplatin, tetraplatin, transplatin, JM335, or JM216. The formation of protein-DNA complexes that contained hMSH2 and hMLH1 was documented by mobility shift assay when nuclear extracts were incubated with DNA platinated with cisplatin but not with oxaliplatin. These results demonstrate a correlation between failure of the DNA mismatch repair proteins to recognize the platinum adduct and low-level resistance, suggesting a role for the DNA mismatch repair system in generating signals that contribute to the generation of apoptotic activity. They also identify the use of drugs whose adducts are not recognized as a strategy for circumventing resistance due to loss of DNA mismatch repair.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Isolation of the ATP-binding human homolog of the arsA component of the bacterial arsenite transporter.

Arsenite resistance in bacteria is mediated by an efflux pump composed of the arsA and arsB gene products. We have isolated the human homolog of the bacterial arsA (hARSA-I), a member of the ATPase superfamily with no transmembrane domain. Southern and Northern analyses indicated the presence of two cross-hybridizing genes in the human genome and expression of hARSA-I in many tissues. A rabbit antiserum raised against a glutathione-S-transferase (GST)/hARSA-I fusion protein identified two cross-reacting proteins of 37 and 42 kDa by Western analysis in two different human cell lines. Overexpression of hARSA-I in the embryonal human kidney 293 cell line was accompanied by overproduction of the 37-kDa protein Biochemical analysis using the GST/hARSA-I fusion protein indicated that hARSA-I is an ATPase analogous to the bacterial ArsA. Thus, hARSA-I is a new eukaryotic member of a highly conserved ATP-binding superfamily of proteins.

Adenosine Triphosphatases↗

PubMed1996

Determinants of tamoxifen sensitivity control the nature of the synergistic interaction between tamoxifen and cisplatin.

The cytotoxic effect of tamoxifen (TAM) was investigated in the T-289 melanoma cell line, as well as the 289 DDP3 cisplatin (DDP)-resistant and the 289 TAM6 TAM-resistant variant melanoma cell lines to determine the effect of drug resistance on synergy. T-289 melanoma cells were made DDP or TAM resistant through chronic exposure to increasing concentrations of the respective drugs. Whereas DDP resistance could be overcome by increasing the concentration of TAM, the development of TAM resistance completely abolished synergy. TAM resistance was not related to the development of estrogen receptors, decreased TAM uptake, or the increased expression of the mdr-1 gene. TAM did not inhibit the action of Topoisomerase 1; however, TAM did induce apoptosis in the 289 melanoma cells. In contrast, TAM did not induce apoptosis in the TAM-resistant variant 289 TAM6 cells. To our knowledge, these are the first data associating TAM resistance with the inhibition of apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Paclitaxel activation of the GADD153 promoter through a cellular injury response element containing an essential Sp1 binding site.

The GADD153 promoter is transcriptionally activated by paclitaxel-induced injury. Promoter deletion from -786 to -85 base pairs relative to the start of transcription had no significant effect on activation, but deletion to the TATA box abolished it. Placement of the 39 bases from -74 to the TATA box (cellular injury response element, CIRE) upstream of the adenovirus E4 TATA box conferred paclitaxel inducibility. The only consensus sequence present in the CIRE is an Sp1 site; mutation of this site inhibited paclitaxel activation. Paclitaxel failed to activate a SV40-driven luciferase construct containing five Sp1 sequences, and Sp1 sites further upstream in the GADD153 promoter were not essential for activation. Pure Sp1 and nuclear extracts from uninjured and paclitaxel-injured cells protected the same region from -62 to -48 bases on the noncoding strand and -74 to -53 on the coding strand. Nuclear extracts shifted the CIRE to the same extent as purified Sp1 but had no effect on a CIRE with a mutated Sp1 site in gel shift assays. Immunodepletion of Sp1 abolished the shift; antibody to Sp1 produced a supershift. These data indicate that paclitaxel activates the GADD153 promoter through a constitutively occupied Sp1 site at -61 bases.

Base Sequence↗

PubMed1996

Loss of DNA mismatch repair in acquired resistance to cisplatin.

Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutations in genes involved in DNA mismatch repair and thereby to resistance to DNA-alkylating agents. Parental cells of the human ovarian adenocarcinoma cell line 2008 expressed hMLH1 when analyzed with immunoblot. One subline selected for resistance to cisplatin (2008/A) expressed no hMLH1, whereas another (2008/C13*5.25) expressed parental levels. Microsatellite instability was readily demonstrated in 2008/A cells but not in 2008 and in 2008/C13*5.25 cells. In addition, the 2008/A cells were 2-fold resistant to methyl-nitro-nitrosoguanidine and had a 65-fold elevated mutation rate at the HPRT locus as compared to 2008 cells, both of which are consistent with the loss of DNA mismatch repair in these cells. To determine whether the loss of DNA mismatch repair itself contributes to cisplatin resistance, studies were carried out in isogenic pairs of cell lines proficient or defective in this function. HCT116, a human colon cancer cell line deficient in hMLH1 function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLH1. Similarly, the human endometrial cancer cell line HEC59, which expresses no hMSH2, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 2 that expresses hMSH2. Therefore, the selection of cells for resistance to cisplatin can result in the loss of DNA mismatch repair, and loss of DNA mismatch repair in turn contributes to resistance to cisplatin.

Adaptor Proteins, Signal Transducing↗

PubMed1996

A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx.

OBJECTIVE: To pilot a targeted chemoradiation protocol for patients with advanced carcinoma of the larynx and pharynx that would circumvent upper aerodigestive tract dysfunction related to major oncologic surgery. DESIGN: Weekly intra-arterial infusions of supradose cisplatin (150 mg/m2 per week x 4) rapidly delivered to the tumor bulk, simultaneous intravenous sodium thiosulfate for systemic drug neutralization, and conventional external-beam irradiation (1.80-2.00 Gy per fraction x 35) were used. Between February 1991 and April 1994, 42 patients were treated who would otherwise have required a major resection of the tongue base, pharyngeal wall, or larynx. MAIN OUTCOME MEASURES: Tumor response, toxic effects, disease control above the clavicle, preservation of the larynx, maintenance of oral nutrition, and overall and disease-related 2-year survival. RESULTS: Three complications were related to the weekly transfemoral superselective intra-arterial procedures performed 160 times. Grade 3 to 4 chemotoxic effects were infrequent, occurring in 9 (5.5%) of 160 cycles, and only 1 patient required a radiotherapy break because of severe mucositis. A complete response in the primary site was obtained in 36 (86%) of 42 patients, 2 of whom had residual disease in the neck. Median follow-up was 13 months (range, 3-46 months). To date, there have been 5 recurrences: 2 regional and 3 distant. The 2-year overall and disease-related survival was 64% and 76%, respectively. The rate of disease control above the clavicle at 2 years was 86%. CONCLUSIONS: We believe this chemoradiation protocol represents an effective management scheme for patients with advanced head and neck cancer while minimizing dysfunction and possibly improving survival.

Adolescent↗

PubMed1996

Cisplatin and taxol activate different signal pathways regulating cellular injury-induced expression of GADD153.

Signal transduction pathways activated by injury play a central role in coordinating the cellular responses that determine whether a cell survives or dies. GADD153 expression increases markedly in response to some types of cellular injury and the product of this gene causes cell cycle arrest. Using induction of GADD153 as a model, we have investigated the activation of the cellular injury response after treatment with taxol and cisplatin (cDDP). Activation of the GADD153 promoter coupled to the luciferase gene and transfected into human ovarian carcinoma 2008 cells correlated well with the increase in endogenous GADD153 mRNA after treatment with taxol but not after treatment with cDDP. Following treatment with cDDP, the increase in endogenous GADD153 mRNA was 10-fold greater than the increase in GADD153 promoter activity. Likewise, at equitoxic levels of exposure (IC80), cDDP produced a 5-fold greater increase in endogenous GADD153 mRNA than taxol. The tyrosine kinase inhibitor tyrophostin B46 had no significant effect on the ability of taxol to activate the GADD153 promoter, but inhibited activation of the GADD153 promoter by cDDP in a concentration-dependent manner. Tyrphostin B46 synergistically enhanced the cytotoxicity of cisplatin; however, the same exposure had no significant effect on the cytotoxicity of taxol. We conclude that (1) taxol and cDDP activate GADD153 promoter activity through different mechanisms; (2) the signal transduction pathway mediating induction by cDDP involves a tyrosine kinase inhibitable by tyrphostin B46; and (3) that inhibition of this signal transduction pathway by tyrphostin synergistically enhances cDDP toxicity.

Antineoplastic Agents↗

PubMed1996

Targeted infusions of supradose Cisplatin with systemic neutralization for carcinomas invading the temporal bone.

In an attempt to improve the dismal prognosis for patients with advanced cancer involving the temporal bone, a regional chemotherapy technique was piloted as part of the multimodality therapy for such patients. Rapid supradose cisplatin infusions selectively delivered to the lesion were given to 14 patients with carcinoma involving the temporal bone. Concurrent systemic cisplatin neutralization was achieved with sodium thiosulfate which permitted the use of cisplatin dose intensity regimens equivalent to fivefold the conventional amount. Four patients received chemotherapy alone, four had concomitant irradiation, and six had subsequent irradiation and/or temporal bone surgery. All patients tolerated the chemotherapy without significant complications or toxicity.All three of the patients with previously untreated disease responded to chemotherapy (2 Crs, 1 PR); three of the seven patients with recurrent disease responded to chemotherapy; and all four patients treated with chemoradiation had a complete response (including one patient with recurrent disease). The median follow-up time was 19 months (range, 5 to 63 months). Nine of the 14 patients are alive, including the 4 who were treated with targeted chemoradiation.The use of targeted high-dose chemotherapy for patients with malignant skull base lesions offers hope for improved outcome, particularly when this regimen is given simultaneously with radiation.

Journal Article↗

PubMed1996

"Decadose" effects of cisplatin on squamous cell carcinoma of the upper aerodigestive tract. II. Clinical studies.

There is evidence that solid tumors rapidly acquire cellular resistance to cisplatin. This resistance is usually mild to moderate and could be circumvented with higher concentrations of drug exposure if ancillary methods were available to avoid systemic cytotoxicity. The purpose of this study was to determine whether a tenfold increase in dose (decadose) would overcome cisplatin resistance. In a clinical trial, response effects of cisplatin at dose intensities ranging from 32.5 to 200 mg/m2 per week, which were delivered by highly selective intra-arterial infusions with a simultaneously administered intravenous neutralizing agent, were measured in 31 patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT). The overall response rate (complete response [CR] and partial response [PR] to cisplatin therapy at dose intensity intervals of 0 to 74, 75 to 149, and 150 to 200 mg/m2 per week were 45.5%, 72.7%, and 100%, respectively. The average received dose intensities for nonresponders and responders (CR and PR) were 57.8 and 120.7 mg/m2 per week, respectively (P = .031). The results indicate that resistance to standard doses of cisplatin by SCC of the UADT, both previously untreated and recurrent, can be substantially overcome with "decadose" cisplatin therapy. Progress toward improving survival of patients with head and neck cancer, and possibly other site-specific malignancies, may be achieved by incorporating decadose cisplatin therapy into a multimodality treatment plan.

Adult↗

PubMed1996

Isolation and characterization of a cisplatin-resistant strain of Schizosaccharomyces pombe.

A cis-diamminedichloroplatinum [DDP (cisplatin)]-resistant population of Schizosaccharomyces pombe was developed through chronic exposure of the 972 h- strain to increasing concentrations of the drug. The resulting cells, designated wtr2, were 5.25-fold resistant to DDP, are resistance was retained by clone isolated from this population in the absence of drug for > or = 5 months. After backcrossing and isolation of a single clone, random spore analysis gave a segregation ratio close to 1:1 for DDP resistance and sensitivity. Tetrad analysis confirmed a mendelian 2:2 segregation, suggesting that a single nuclear gene was responsible for the DDP-resistant phenotype. Stable diploids obtained from the mating of a resistant spore carrying the ade6-216 marker with the mei2-102-ade6-210 meiosis-deficient mutant remained resistant, indicating that the resistant phenotype was expressed dominantly. There was no difference between the accumulation of the DDP analog [3H]dichloro(ethylenediamine)-platinum(II) into whole cells derived from the sensitive and the resistant spores obtained from the last backcross. The resistant clones from a single tetrad did not have an increased level of glutathione and were collaterally sensitive to cadmium and arsenite. We conclude that in S. pombe, a stable and dominant DDP-resistant phenotype can be mediated by a single allele, that the phenotype is not accompanied by cross-resistance to cadmium or arsenite, and that the mechanism is not associated with a significant alteration in glutathione level or DDP uptake.

Alleles↗

PubMed1995

Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases.

PURPOSE: To study the results of intralumbar administration of chemotherapeutic agents for the treatment of neoplastic meningitis and to determine how these results relate to the variable and often subtherapeutic drug concentrations in the ventricular cerebrospinal fluid (CSF) compartment. Ventricular and lumbar pharmacokinetic studies were done following intralumbar administration of DTC-101, an extended-release formulation of cytarabine. PATIENTS AND METHODS: Nine patients (age range, 23 to 67 years; median age, 42 years) with leptomeningeal metastases were treated with 18 courses of intralumbar DTC-101. Eight patients who were treated with 14 courses underwent pharmacokinetic CSF sampling from the lumbar sac and lateral ventricle. Cytarabine concentrations were determined by using high-pressure liquid chromatography. RESULTS: Following intralumbar administration of DTC-101, therapeutic free cytarabine concentrations were achieved rapidly in both of the ventricular and lumbar CSF compartments and maintained for 2 weeks. The mean pharmacokinetic parameters of free cytarabine in the lumbar and ventricular CSF compartments were as follows: maximum concentration, 226 and 6.06 mg/L; half-life, 277 and 130 hours; and area under the concentration vs time curve, 4120 and 598 micrograms/h per milliliter, respectively. CONCLUSIONS: Intralumbar administration of DTC-101 results in extended cytotoxic free cytarabine concentrations in both of the lumbar and ventricular regions of CSF and allows an every-other-week drug-dosing schedule.

Adult↗

PubMed1995

Selective intra-arterial infusion of high-dose cisplatin in patients with advanced head and neck cancer results in high tumor platinum concentrations and cisplatin-DNA adduct formation.

A group of 23 patients with advanced head and neck cancer were treated with highly selective intra-arterial (IA) cisplatin 150 mg/m2 delivered rapidly through microcatheters. The systemic effects of cisplatin were neutralized by concurrent administration of sodium thiosulfate. Two-to-threefold higher tumor platinum contents were detected in tumor biopsies after selective IA cisplatin administration compared to historical controls (treated with 100 mg/m2 IA). Cisplatin-induced DNA modification in human tumor biopsies was quantitated using the antiserum NKI-A59. High levels of cisplatin DNA adducts were detected which correlated linearly with the tumor platinum content (r2 = 0.62). The addition of radiotherapy to this high dose intensity cisplatin treatment resulted in a 92% complete response (CR) rate (12 of 13 patients achieved a CR). Since no difference in tumor platinum content was detected between patients receiving or not receiving radiotherapy (13 and 10 patients, respectively), but the response rate was substantially different (12 CR and 1 partial response with radiotherapy versus 6 partial and 4 non-responders without radiotherapy), these data suggest that the high platinum levels achieved by selective IA infusion were sufficient to produce enough interaction with radiotherapy to cause a 92% CR rate. Whether this interaction is additive or synergistic is as yet unclear.

Antineoplastic Agents↗

PubMed1995

Synergistic interaction between cisplatin and tamoxifen delays the emergence of cisplatin resistance in head and neck cancer cell lines.

The interaction between cisplatin (cDDP) and tamoxifen (TAM) was evaluated in the human head and neck squamous-carcinoma cell lines UM-SCC-10B and UM-SCC-5. Synergy between cDDP and TAM was demonstrated in the UM-SCC-10B cell line. Concordant with the synergistic effect between cDDP and TAM, the rate of development of resistance to cDDP was delayed when selections were performed in the presence of TAM. However, in the UM-SCC-5 cell line, TAM was neither synergistic nor did it delay the development of cDDP resistance. The difference with respect to the synergistic interaction of cDDP with TAM and the effect on the development of cDDP resistance in the UM-SCC-10B and UM-SCC-5 cell lines was not related to any significant difference in the accumulation of the cDDP analog [3H]-cis-dichloro(ethylenediamine)platinum(II) (DEP), drug sensitivity [concentrations inhibiting colony formation by 50% (IC50 values) were 6.5 and 7.2 microM for cDDP and 3.5 and 3.2 microM for TAM, respectively], the number of estrogen and progesterone receptors (negative in both cell lines), the number of antiestrogen binding sites (404 +/- 85 and 353 +/- 24 fmol/mg protein, respectively), or the affinity of TAM for these binding sites (1.7 and 1.5 nM, respectively). Importantly, however, we demonstrated that TAM can delay the emergence of resistance to cDDP in head and neck carcinomas and that this effect is linked to the nature of the interaction between cDDP and TAM.

Binding Sites↗

PubMed1995

Enhancement of drug sensitivity of human malignancies by epidermal growth factor.

We have previously shown that epidermal growth factor (EGF) enhances the in vitro and in vivo sensitivity of human ovarian carcinoma 2008 cells to cisplatin. EGF was found to enhance selectively the in vivo toxicity of cisplatin to 2008 cell xenografts without altering the toxicity of cisplatin to non-malignant target tissues such as the kidney or bone marrow. We now show that recombinant human EGF (rhEGF) enhances the cisplatin sensitivity of cell lines representative of many other types of malignancies in addition to ovarian carcinoma, including cancers of the head and neck, cervix, colon, pancreas and prostate, as well as non-small-cell carcinoma of the lung. In addition, rhEGF was found to sensitise cells to other platinum-containing drugs and several other classes of chemotherapeutic agents. rhEGF sensitised 2008 cells not only to cisplatin, but also to carboplatin and tetraplatin, as well as taxol, melphalan and 5-fluorouracil. We conclude that modulation of drug sensitivity by rhEGF is observed in cell lines representative of many human malignancies and for multiple classes of chemotherapeutic agents, indicating that it alters one or more components of the cellular damage response that are both common between cell lines and classes of drugs and fundamental to survival.

Antineoplastic Agents↗

PubMed1995

A phase II trial of intraperitoneal high-dose carboplatin and etoposide with granulocyte macrophage-colony stimulating factor support in patients with ovarian carcinoma.

Based upon results obtained in a Phase I study, we conducted a Phase II trial of high-dose CBDCA and etoposide administered via the intraperitoneal (IP) route in patients with ovarian cancer. CBDCA at a dose of 600 mg/m2 and etoposide at a dose of 400 mg/m2 were administered rapidly into the peritoneal cavity. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of D5W and administered intraperitoneally as rapidly as possible. On days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/day. A total 53 courses of treatment was administered to 18 patients; 9 of 13 patients (69%) with evaluable disease demonstrated evidence consistent with a partial response; however, the majority were response determined by a decrease in tumor marker (CA-125). One patient who had pathologic evidence of disease at second look laparotomy, but no measurable disease, was treated and shown at subsequent reexploration to have no further evidence of disease. This patient remains free of disease at 17+ months. The toxicity encountered in this trial was formidable, resulting in the removal of 78% of the patients from the study prior to completing 6 cycles of therapy.

Antineoplastic Combined Chemotherapy Protocols↗