Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

At least 91 records · Page 5Linked to original sources

PubMed1995

Cross-resistance between cisplatin, antimony potassium tartrate, and arsenite in human tumor cells.

Cross-resistance between cisplatin (DDP) and metalloid salts in human cells was sought on the basis that mechanisms that mediate metalloid salt cross-resistance in prokaryotes are evolutionarily conserved. Two ovarian and two head and neck carcinoma cell lines selected for DDP resistance were found to be cross-resistant to antimony potassium tartrate, which contains trivalent antimony. The DDP-resistant variant 2008/A was also cross-resistant to arsenite but not to stibogluconate, which contains pentavalent antimony. A variant selected for resistance to antimony potassium tartrate was cross-resistant to DDP and arsenite. Resistance to antimony potassium tartrate and arsenite was of a similar magnitude (3-7-fold), whereas the level of resistance to DDP was greater (17-fold), irrespective of whether the cells were selected by exposure to DDP or to antimony potassium tartrate. In the resistant sublines, uptake of [3H]-dichloro(ethylenediamine) platinum(II) was reduced to 41-52% of control, and a similar deficit was observed in the accumulation of arsenite. We conclude that DDP, antimony potassium tartrate, and arsenite all share a common mechanism of resistance in human cells and that this is due in part to an accumulation defect.

Anions↗

PubMed1994

Cross-resistance between cisplatin and antimony in a human ovarian carcinoma cell line.

The metal compound cisplatin (DDP) is a widely used anticancer agent but naturally occurring and acquired resistance to DDP limits its effectiveness. Resistance is associated with a decreased accumulation of DDP and increased levels of glutathione and metallothioneins. Such changes also serve as protective and detoxification mechanisms for other metal salts in prokaryotes and lower eukaryotes. The aim of this study was to find metal salts for which the cross-resistance profile was the same as for DDP in sublines of the parental 2008 human ovarian carcinoma cells selected with either DDP (2008/C13*5.25) or CdCl2 and ZnCl2 (2008/MT). Among the metal salts tested the resistance profile of trivalent antimony most closely resembled that of DDP. DDP-selected cells were 15-fold resistant to DDP and 4.4-fold cross-resistant to antimony potassium tartrate, whereas of the cations tested (Cd2+, Zn2+, Ni2+ and Co2+) cross-resistance was observed only for Cd2+ (2.4-fold). When 2008 cells were selected for resistance to antimony (6.6-fold) they were found to be 16-fold cross-resistant to DDP. Accumulation of the DDP analogue cis-[3H]dichloro(ethylenediamine)platinum(II) was 59% lower in the DDP-selected subline and 48% lower in the antimony-selected variant than in the parental cell line. We conclude from the mutual cross-resistance to DDP and antimony potassium tartrate and from the impaired uptake of [3H]DEP in both the DDP and antimony-selected variants that DDP and antimony share a common mechanism of resistance. The significance of this observation lies in the fact that several evolutionarily conserved mechanisms for antimony detoxification are already known in lower organisms which may point the way to identification of additional DDP resistance mechanisms in mammalian cells.

Antimony↗

PubMed1994

A phase I trial of intraperitoneal carboplatin and etoposide with granulocyte macrophage colony stimulating factor support in patients with intraabdominal malignancies.

BACKGROUND: Although somewhat controversial, there are data to suggest that patients with ovarian cancer may experience a survival advantage if the dose intensity of platinum-containing regimens can be maximized. Administration of chemotherapeutic agents via the intraperitoneal route offers the opportunity to increase dose intensity of several chemotherapeutic agents. METHODS: The authors conducted a Phase I trial of intraperitoneal carboplatin and etoposide in combination with granulocyte macrophage colony stimulating factor (GM-CSF) in an attempt to determine the maximum tolerated dose of carboplatin. The starting dose for carboplatin was 300 mg/m2 and for etoposide 400 mg/m2. The dose of carboplatin was escalated while the etoposide was maintained at the initial dose. 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 dextrose (D5W) and administered intraperitoneally (IP) 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/d. RESULTS: Unacceptable hematologic toxicity was encountered at a carboplatin dose of 800 mg/m2; therefore, a carboplatin dose of 600 mg/m2 is recommended for Phase II studies. An overall response rate of 54% with a complete response rate of 17% was observed in patients with ovarian cancer. The overall response rate for all patients was 45%. CONCLUSION: Because of the significant toxicity encountered in this study, it is recommended that this regimen be used only in the context of a clinical study. The recommended Phase II study dose for this combination is carboplatin 600 mg/M2 and a total dose of etoposide 400 mg/M2 total dose given as three equal parts IP over 3 days. GM-CSF should begin on Day 4 at a dose of 500 micrograms/m2/day subcutaneously and should continue until the absolute neutrophil count is greater than 1000 granulocytes on 3 successive days.

Abdominal Neoplasms↗

PubMed1994

Cellular pharmacology of dichloro(ethylenediamine)platinum(II) in cisplatin-sensitive and resistant human ovarian carcinoma cells.

The cellular pharmacology of the tritium-labeled cisplatin analogue dichloro(ethylenediamine)platinum(II) ([3H]DEP) was compared in cisplatin-sensitive 2008 and resistant 2008/C13*5.25 human ovarian carcinoma cells. The cellular content of total [3H], ultrafiltrable [3H], and free native [3H]DEP was measured during and following incubation with 5 microM [3H]DEP. While the rate constant for [3H]DEP uptake in the resistant cells was reduced to 25% of that in the sensitive cells, DNA intrastrand adduct formation was reduced even further to 11%, indicating the presence of defects in both uptake and the ability of intracellular drug to access or react with DNA. The latter could not be accounted for by enhanced repair. Together, these defects were sufficient to account for the 11-fold level of resistance. At steady state, the intracellular to extracellular concentration ratio for native [3H]DEP was 7.7 in the sensitive cells and 11.7 in the resistant cells, suggesting the presence of a trapping or concentrative mechanism. Thus, despite the slower initial influx, the resistant cells eventually accumulated more free [3H]DEP than the sensitive cells. We conclude that the resistant phenotype in these cells is accounted for primarily by impaired uptake and decreased reaction of [3H]DEP with DNA rather than by changes in efflux or DNA repair.

Cisplatin↗

PubMed1994

Cisplatin sensitivity correlates with its ability to cause cell cycle arrest via a wee1 kinase-dependent pathway in Schizosaccharomyces pombe.

Mutants of Schizosaccharomyces pombe were used to define genes involved in the cell cycle arrest produced by cisplatin (DDP), an agent that causes both DNA damage and inhibition of DNA synthesis. Previous work has demonstrated that strains with defective or absent wee1+ function fail to arrest in G2 when DNA is damaged, but do arrest when DNA synthesis is inhibited (Rowley et al., 1992a, Nature, 356:353-355). Strains defective in wee1+ function, or in the ability of the wee1+ kinase to regulate cdc2, failed to arrest following DDP exposure, as did a rad1-1 mutant. All strains failing to arrest in G2 were hypersensitive to DDP. Thus, DNA damage rather than inhibition of DNA synthesis is causative of DDP-induced cell cycle arrest. In addition, this work shows that the wee1+ and rad1+ gene products are required for successful DDP-induced arrest, and suggests that the ability of S. pombe to arrest is a major determinant of sensitivity to DDP.

Cell Cycle↗

PubMed1994

A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer.

A phase III study was conducted comparing intraperitoneal (ip) versus intravenous (iv) cisplatin-based therapy for patients with newly diagnosed ovarian cancer to determine if the pharmacologic advantage of ip delivery could be translated into an improved response and survival rate. Twenty-nine patients were randomized to receive six cycles of ip cisplatin 200 mg/m2 plus ip etoposide 350 mg/m2 with iv thiosulfate protection given every 4 weeks; thirty-three patients were randomized to receive six cycles of iv cisplatin 100 mg/m2 plus iv cyclophosphamide 600 mg/m2 administered every 3 weeks. Patients were stratified by stage (IIC-IV) and size of residual disease (> or < or = 1 cm). The study was conducted in a community-wide setting. The complete response in evaluable patients was 48% in the ip group and 52% in the iv group. The surgical complete response rate for all patients on study, underestimated because not all patients in complete clinical remission had a second-look laparotomy, was 31% in the ip group and 33% in the iv group. There was no difference in the response rates between the treatment arms as a function of residual disease < or = or > 1 cm. With a median follow-up of 46 months (range 21-70 months) there is no difference in response duration or survival. Both regimens were well tolerated with comparable hematologic and nonhematologic toxicity.

Adult↗

PubMed1994

Role of metallothionein in carcinogenesis.

Metallothionein (MT) is a low-molecular-weight protein (6800 Da) and one-third of its amino acids are cysteine residues. The 20 cysteines coordinate 7 metal atoms (zinc, copper, and/or cadmium). This protein is extremely inducible by metals as well as a number of organic compounds. MT is though to be an important intracellular storage site for zinc and possibly other essential trace elements. In addition, tolerance to cadmium toxicity is often due to the induction of MT, which sequesters cadmium and lowers its concentration at critical intracellular sites. Recently it has been proposed that MT might play important roles in several aspects of the carcinogenic process. In this context a symposium was held recently on this topic at the 1993 Annual Society of Toxicology Meeting. At this symposium Dr. Cherian discussed the expression of MT in various human tumors and its use as a potential marker of tumor differentiation or cell proliferation. Dr. Imura provided data illustrating that induction of MT can be used as an adjunct in cancer chemotherapy, in preventing toxicity caused by gamma-irradiation or cisplatin (CDDP) and other chemotherapeutics. Induction of MT has been suggested to be an important mechanism of resistance of tumor cells to chemotherapeutic agents, such as CDDP. This is controversial, and various views on this topic were presented by Drs. Howell, Lazo, and Koropatnick. Dr. Waalkes then discussed the role of MT in the carcinogenic and anticarcinogenic effects of metals.

Animals↗

PubMed1994

Enhancement of the cytotoxicity of cisplatin by the cholecystokinin antagonist MK-329 in a human pancreatic cancer cell line.

Cholecystokinin (CCK) is an important trophic hormone for the pancreas, and CCK receptors are present on pancreatic carcinoma cells. We sought to determine whether either CCK itself or an antagonist of CCK could modulate the sensitivity of the human pancreatic cell line MIA-PaCa2 to cisplatin (DDP). The IC50 for a 1-h exposure to DDP was 35.3 +/- 3.2(SD) microM. Exposure to CCK8 octapeptide at physiologic and supra-physiologic concentrations did not alter the sensitivity of MIA-PaCa2 cells to DDP. The CCK receptor antagonist MK-329 was directly cytotoxic to the MIA-PaCa2 cells on a constant exposure schedule with an IC50 of 9.5 +/- 1.4 (SD) microM. MK-329 enhanced the sensitivity of MIA-PaCa2 cells to DDP by a factor of 3.5, and the interaction between DDP and MK-329 was shown to be synergistic by median-effect analysis. At a level of 50% cell kill, the combination index was 0.58 +/- 0.10. The ability of MK-329 to sensitize cells to DDP was schedule-dependent and required prolonged exposure to the antagonist following a 1-h exposure to DDP. MK-329 had no effect on the uptake of a radiolabeled analog of cisplatin ([3H]-dichloro(ethylenediamine)platinum) and did not affect intracellular glutathione content. MK-329 had no effect on the cell-cycle-phase distribution of MIA-PaCa2 cells and did not alter the DDP-induced cell-cycle perturbations. The cytotoxic effect of MK-329 and its ability to interact synergistically with DDP could not be reversed by CCK. We conclude that MK-329 is directly cytotoxic to pancreatic carcinoma cells and can enhance their sensitivity to DDP by a mechanism not related to its ability to antagonize the CCK receptor.

Antineoplastic Agents↗

PubMed1994

Signaling and drug sensitivity.

Even though alterations in receptor and nonreceptor kinases are involved in the development of human cancer, many cancer cell lines still retain their responsiveness to growth factors. We have investigated the hypothesis that cellular signaling events regulate the sensitivity of cancer cells to chemotherapeutic agents. In 2008 human ovarian carcinoma cells, activation of a number of different transduction pathways resulted in a 2 to 4-fold increase in the sensitivity to cisplatin. These signaling events include pathways activated by the epidermal growth factor (EGF) receptor, tumor necrosis factor alpha (TNF alpha) receptor, bombesin receptor, protein kinase A (PKA), and protein kinase C (PKC). Enhanced sensitivity to chemotherapeutic agents is presumed to be mediated by phosphorylation of critical target protein(s). beta-tubulin has been identified as one such target for the protein kinase signaling cascade. For other signal transduction pathways the key substrates that regulate drug sensitivity have not yet been identified. Recent work has shown that DNA damaging agents activate signaling cascades one of which involves the Src, Ras, and Raf proteins as intermediates and results in induction of a number of genes, including c-fos, c-jun, and the growth arrest and DNA damage-inducible (gadd) genes. This signaling cascade has been shown to involve activation of protein kinase C and to have a protective function. With the growing understanding of how signaling events relate to damage response and drug sensitivity, new and potentially useful strategies for modulating drug sensitivity are evolving.

Animals↗

PubMed1994

A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer.

BACKGROUND: Hypothesizing that cisplatin (DDP) drug resistance is dose dependent and the radiosensitizing effect of DDP is clinically beneficial, we conducted a chemoradiation protocol using extremely high doses of DDP delivered intra-arterially (IA) to locally advanced head and neck tumors. PATIENTS AND METHODS: Twenty-nine patients with untreated stage IV disease received 4 weekly infusions of 150 mg/m2, simultaneous systemic DDP neutralization with intravenous (IV) bolus sodium thiosulfate, and concomitant radiotherapy (180 to 200 cGy/day x 35 fractions). RESULTS: The complete response rate of the 24 evaluable patients as determined with repeat biopsies was 23/24 (96%). Of the 29 patients evaluable for toxicity, central nervous system complications related to the infusion technique occurred with 2/110 infusions, both of which were reversible. The rate of grade III to IV chemotoxicity was 13%. The median length of follow-up was 22 months. There have been 6 recurrences: 1 local; 3 regional; and 2 at distant sites. The projected overall and disease-free 3-year survival was 88% and 53%, respectively. CONCLUSION: We conclude that the combination of rapid selective delivery of supradose DDP/IV thiosulfate neutralization and concomitant radiotherapy can be safely and effectively applied to patients with advanced head and neck cancer. Preliminary survival analysis indicates that this approach may improve the prognosis for patients with an otherwise devastating disease.

Adult↗

PubMed1994

Tamoxifen delays the development of resistance to cisplatin in human melanoma and ovarian cancer cell lines.

The development of resistance to cisplatin (DDP) occurs rapidly both in vitro and in vivo, and constitutes a major obstacle to effective therapy. We have previously demonstrated that there is a highly synergistic interaction between tamoxifen (TAM) and DDP against cell lines representative of three different human cancers: melanoma, ovarian carcinoma and small-cell lung cancer. The purpose of these studies was to determine if TAM interferes with the development of resistance to DDP. T-289 melanoma cells and 2008 ovarian cancer cells were cultured with increasing concentrations of DDP +/- TAM in an attempt to induce resistance to DDP. At various time points the cells were removed from culture and the degree of resistance to DDP was quantitated. Concurrent exposure to TAM and DDP decreased both the rate and the absolute magnitude of resistance to DDP in both melanoma and ovarian cancer cell lines. In the T-289 cell line the rate was decreased by a factor of 3.4 +/- 1.4 (P < 0.05), while in the 2008 cell line the rate was decreased by a factor of 2.4 (P < 0.01). TAM decreases the rate as well as the absolute magnitude of in vitro resistance to DDP in both melanoma and ovarian cancer cell lines. These data suggest that the concurrent administration of TAM and DDP may result in a delay in the development of resistance to DDP which may have important clinical implications in the design of DDP-containing regimens.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Enhancement of sensitivity to platinum(II)-containing drugs by 12-O-tetradecanoyl-phorbol-13-acetate in a human ovarian carcinoma cell line.

Sensitivity to platinum-containing drugs is believed to be a function of how much drug enters the cell, the extent of DNA adduct formation and the rate at which DNA is repaired. Activation of protein kinase C by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was found to enhance the sensitivity of human ovarian carcinoma 2008 cells to cisplatin (DDP), carboplatin (CBDCA) and (glycolato-O,O') diammineplatinum(II) (254-S). TPA was able to enhance the sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of the three drugs to the same extent as for the 2008 cells. TPA produced no significant change in the uptake of [3H]cis-dichloro(ethylenediamine)-platinum(II). ([3H]DEP) or CBDCA. It did not alter glutathione content or glutathione-S-transferase activity, and induced rather than suppressed metallothionein IIA mRNA levels. TPA did increase the formation of intrastrand guanine-guanine cross-links by a factor of 1.5 +/- 0.3 (s.d.), and reduced the fraction of intrastrand adducts removed from DNA over the subsequent 24 h by a factor of 1.3 +/- 0.2 (s.d.) (n = 4; P < 0.05), however, these effects were too small to account for the degree of TPA-induced sensitisation. These results indicate that the mechanism of TPA-induced sensitisation is not specific to any one structural form of platinum-containing drug, and that it is not readily explicable on the basis of an effect on the four major parameters currently believed to regulate DDP sensitivity.

Carboplatin↗

PubMed1994

Induction of the growth arrest and DNA damage-inducible gene GADD153 by cisplatin in vitro and in vivo.

The inability to assess the extent of tumour damage immediately following treatment is a major clinical obstacle to improving the management of cancer patients. Normally, the effectiveness of chemotherapy or radiation therapy cannot be determined for at least several weeks after treatment. We studied the increase in mRNA of the growth arrest and DNA damage-inducible gene GADD153 in human 2008 ovarian carcinoma cells in vitro and in vivo to determine whether treatment-induced increases in the level of GADD153 mRNA could be used as a marker of the extent of tumour damage. GADD153 mRNA was increased in a transient, dose-dependent manner by cisplatin (DDP) when the tumour cells were grown both in vitro and as tumour xenografts in nude mice. The magnitude of induction of GADD153 mRNA did not vary significantly between different 2008 xenografts treated with equal doses of DDP, and GADD153 mRNA induction correlated with the degree of in vitro cytotoxicity for two different schedules of drug exposure. DDP increased GADD153 mRNA levels in melanoma and head and neck xenograft models as well. We conclude that the increase in GADD153 mRNA can be used to detect tumour injury at time points as short as 24 h after administration of DDP.

Animals↗

PubMed1994

Synergistic interaction between cisplatin and taxol in human ovarian carcinoma cells in vitro.

Taxol, a unique tubulin active agent, was found to demonstrate a marked schedule-dependent synergistic interaction with cisplatin (DDP) in the killing of human ovarian carcinoma 2008 cells in vitro as determined by median effect analysis. The interaction was highly synergistic when 19 h taxol exposure was followed by 1 h concurrent exposure to taxol and DDP. The combination indices (CIs) on this schedule were 0.11 +/- 0.1, 0.25 +/- 0.15 and 0.39 +/- 0.14 at 20%, 50% and 80% cell kill respectively. However, the interaction was antagonistic when 1 h exposure to DDP was followed by 20 h exposure to taxol, or when cells were exposed to DDP and taxol for 1 h concurrently. When taxol preceded DDP, synergy was also observed with the 11-fold DDP-resistant 2008/C13*5.25 subline, which yielded CI values of 0.21 +/- 0.02, 0.30 +/- 0.11 and 0.31 +/- 0.17 at 20%, 50% and 80% cell kill respectively. At an IC50 concentration, taxol had no effect on [3H]cis-dichloro(ethylenediamine) platinum uptake, on the permeability of the plasma membrane or on glutathione or metallothionein levels in 2008 or 2008/C13*5.25 cells. Mitotic arrest in these cells was observed only at taxol concentrations well above those required for synergy with DDP, suggesting that the mechanism underlying the synergistic interaction was not a taxol-induced alteration in cell cycle kinetics. Of additional interest was the fact that the 2008/C13*5.25 cells were hypersensitive to taxol, and that this was partially explained by an alteration in the biochemical pharmacology of taxol. Although cellular taxol accumulation reached steady state within 2 h in both cell lines, taxol efflux was slower and the taxol was more extensively bound in 2008/C13*5.25 cells than in 2008 cells. In addition, the 2008/C13*5.25 cells had only 55% of the parental levels of beta-tubulin content. However, in another pair of DDP-sensitive and -resistant ovarian cell lines no taxol hypersensitivity and no change in beta-tubulin content was observed, indicating that the DDP-resistant and taxol-hypersensitive phenotypes do not segregate together. We conclude that taxol interacts synergistically with DDP in a manner that is highly schedule dependent, and that the hypersensitivity of 2008/C13*5.25 cells no taxol is unrelated to the mechanism of synergy. These in vitro observations suggest that drug schedule will be an important determinant of the activity and toxicity of the DDP and taxol drug combination in clinical studies.

Carcinoma↗

PubMed1994

Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer.

PURPOSE: To determine the maximum dose-intensity of cisplatin (DDP) that could be administered by selective intraarterial (IA) infusion in combination with systemic sodium thiosulfate neutralization to patients with head and neck carcinoma. PATIENTS AND METHODS: Forty-two patients (23 untreated stage III/IV, 19 recurrent) received highly selective IA DDP, rapidly delivered through microcatheters placed angiographically, to a maximum dose-intensity of 200 mg/m2/wk. Concurrently, the systemic effects of DDP were neutralized by intravenous (IV) bolus sodium thiosulfate. RESULTS: Problems related to the infusion technique occurred in eight of 140 courses, all of which were inconsequential. The rates of reversible grade I/II and grade III/IV toxicity were 14.8% and 1.1%, respectively. Dose-limiting toxicity, which consisted of severe electrolyte loss, occurred at a dose of 200 mg/m2/wk. The maximum-tolerated dose of DDP was 150 mg/m2 administered weekly for four doses. The overall and complete response rates in 38 assessable patients were 19 of 22 (86%) and nine of 22 (41%) for stage III/IV untreated tumors and 10 of 16 (62%) and four of 16 (25%) for patients with recurrent disease, respectively. CONCLUSION: This pharmacologic strategy permits the selective and rapid delivery of extremely high doses of DDP to head and neck carcinomas with minimal procedural complications, low systemic toxicity, and high tumor response rates.

Adult↗

PubMed1994

Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells.

Approximately 30% of human breast and ovarian cancers have amplification and/or overexpression of HER-2/neu gene which encodes a cell surface growth-factor receptor. Overexpression of this receptor, p185HER-2/neu, is associated with poor outcome and may predict clinical response to chemotherapy. Antibodies to HER-2/neu receptor have a cytostatic effect in suppressing growth of cells with overexpression of p185HER-2/neu. To elicit a cytocidal effect, therapy with antireceptor antibody was used in combination with the DNA-damaging drug, cisplatin, and this combined treatment produced a synergistic decrease in cell growth. In addition, antibody mediated an increased sensitivity to cisplatin in drug-resistant ovarian carcinoma cells containing multiple copies of HER-2/neu gene. To evaluate the mechanism for this synergy, unscheduled DNA synthesis was measured in cancer cells using incorporation of [3H]thymidine and autoradiography, and formation and repair of cisplatin-induced DNA adducts was also measured. Treatment with cisplatin led to a marked, dose-dependent increase in unscheduled DNA synthesis which was significantly reduced by combined treatment with antireceptor antibody in HER-2/neu-overexpressing cells. Therapy with antibody to HER-2/neu receptor also led to a 35-40% reduction in repair of cisplatin-DNA adducts after cisplatin exposure and, as a result, promoted drug-induced killing in target cells. This phenomenon which we term receptor-enhanced chemosensitivity may provide a rationale for more selective targeting and exploitation of overexpressed growth factor receptors in cancer cells, thus leading to new strategies for clinical intervention.

Animals↗

PubMed1993

Tamoxifen modulation of cisplatin cytotoxicity in human malignancies.

Recent clinical trials have indicated that addition of tamoxifen (TAM) to a combination of cisplatin (DDP), carmustine and dacarbazine markedly increases the overall objective response rate of patients with metastatic malignant melanoma. Previous studies have determined that there is remarkable synergy between TAM and DDP in a human melanoma cell line T-289. Using the technique of median effect analysis, in clonogenic assay, we observed a highly synergistic interaction between TAM and DDP. To determine whether or not this synergistic interaction was unique to human melanomas, or is generally observed in other types of malignancy, we examined the nature of this interaction using a human ovarian carcinoma and small cell lung cancer cell line. Synergy was observed in both cell lines. In the case of all 3 types of malignancy, synergy was observed at concentrations of both TAM and DDP that can be achieved in patients. Our results demonstrate that cytotoxic synergy between the DDP and TAM is observed in cell lines established from multiple types of human malignancies. It is important to note that the synergy between TAM and DDP is not dependent on the presence of estrogen or progesterone receptors. Since TAM is well tolerated by patients, it is particularly attractive as a potential agent with which to sensitize human tumors to DDP.

Carcinoma, Small Cell↗

PubMed1993

Tamoxifen modulation of cisplatin resistance in patients with metastatic melanoma. A biologically important observation.

BACKGROUND: Treatment with the four-drug combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and tamoxifen (TAM) has resulted in an overall response rate of more than 50% in patients with metastatic melanoma. Deletion of TAM from the regimen resulted in a decrease in the response rate to 10%, suggesting an important role for TAM. The authors have subsequently demonstrated that TAM is highly synergistic with DDP in a human melanoma cell line, T-289, which supports the clinical observation that TAM is important in this regimen. The authors conducted a clinical trial to determine whether the addition of TAM can overcome established DDP resistance in patients with malignant melanoma. METHODS: Patients with metastatic melanoma were initially treated with DDP 100 mg/m2 alone until they demonstrated DDP resistance. On the next cycle of treatment, patients received TAM 40 mg by mouth four times a day on the day before DDP treatment followed by 20 mg by mouth daily for the rest of the 3-week cycle plus the same dose of DDP. RESULTS: Among 24 patients treated with DDP alone there were one complete and two partial responses. Twenty patients, in whom single-agent DDP failed, were treated with the combination of TAM and DDP. Of these 20 patients, 19 were evaluable for response. Among these 19 patients, there were three partial responses (16%) and three mixed responses (16%), for an overall response rate of 32% (0% was expected) (P < 0.001). If the three mixed responses are eliminated, the statistical significance is of borderline significance (P = 0.058). CONCLUSIONS: The addition of TAM to DDP can overcome established DDP resistance in a subset of patients with metastatic melanoma.

Adult↗