PubMed Health⌕ Search

Biomedical subjects

C Erlichman

Publications and source records attributed to C Erlichman.

At least 37 records · Page 2Linked to original sources
PubMed1999

Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors.

Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens).

Adult↗
PubMed1999

A phase I trial of MTA and gemcitabine in patients with locally advanced or metastatic cancer.

MTA has demonstrated activity in breast, lung, bladder, and gastrointestinal malignancies in early clinical trials. Gemcitabine is a cytotoxic pyrimidine antimetabolite with broad activity against solid tumors. We have demonstrated sequence-dependent in vitro cytotoxic synergy when gemcitabine exposure preceded MTA exposure in cultured human HCT-8 colon carcinoma cells. A phase I study testing this synergy in patients is in progress. To date, 14 patients with solid tumors have received 42 courses of treatment at a fixed gemcitabine dose of 1,000 mg/m2 on days 1 and 8 and escalating doses of MTA (200, 300, and 400 mg/m2) given 90 minutes after gemcitabine on day 1. Courses are repeated every 3 weeks. The median number of courses received is three (range, one to seven). National Cancer Institute Common Toxicity Criteria grade 4 hematologic toxicity lasting less than 5 days has been leukopenia and neutropenia. Mild to moderate nonhematologic toxicities include arthralgia, nausea, fatigue, fever, rash, and liver function test abnormalities. One partial response occurred in a patient with previously treated metastatic gallbladder cancer. Dose escalation continues.

Adult↗
PubMed1998

Molecular markers in male breast carcinoma.

BACKGROUND: In contrast to female breast carcinoma, information regarding the prevalence and prognostic information of new molecular markers is limited in male breast carcinoma. The objective of this study was to assess the degree of expression and prognostic value of estrogen receptors (ER), progesterone receptors (PR), androgen receptors (AR), bcl-2, p53, HER-2/neu, cyclin D1, and MIB-1 in a cohort of male breast carcinoma patients. METHODS: A computerized search of the medical index, tumor registry, and tissue registry was used to identify 111 male patients with a diagnosis of primary adenocarcinoma of the breast seen between 1950-1992 at the Mayo Clinic. Of these, 77 patients had adequate tissue specimens available for the immunohistochemical analysis of the markers. Immunoperoxidase staining was performed by an automated avidin-biotin complex method. Progression free (PFS) and overall (OS) survival distributions were estimated using the Kaplan-Meier method. The log rank test was used to determine whether any patient characteristic, tumor feature, or molecular marker was associated significantly with PFS or OS. RESULTS: The majority of tumor specimens were positive for ER (91%), PR (96%), AR (95%), and bcl-2 (94%). Fewer positive specimens were found for cyclin D1 (58%), MIB-1 (38%), HER-2/neu (29%), and p53 (21%). The 5-year PFS and 10-year OS for the entire patient cohort was estimated to be 66% (95% confidence interval [CI], 57-77%) and 38% (95% CI, 29-50%), respectively. PFS was decreased significantly for those patients with tumors staining positively for MIB-1 (P=0.012) or negatively for cyclin D1 (P=0.009). OS was not found to differ significantly with respect to these markers. CONCLUSIONS: The nearly universal expression of hormone receptors in these tumors suggests a central role for endogenous hormones in male breast carcinoma. The high degree of AR expression would suggest that antiandrogen therapy should be explored further. The high frequency of bcl-2 positivity may implicate antiapoptotic mechanisms in the carcinogenesis of male breast carcinoma. The finding of decreased PFS in MIB-1 positive tumors supports the role of proliferative activity as a negative prognostic factor in male breast carcinoma. Positive cyclin D1 expression is associated with increased PFS in male breast carcinoma patients, which suggests that interactions among cell cycle regulatory proteins may be important in this disease.

Adult↗
PubMed1998

Effect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: elevated dTTP pools and enhanced cytotoxicity.

PURPOSE: To determine the effect of combined treatment with 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan) and 5-fluorouracil/ folinic acid (5FU/FA) in vitro using HCT-8 human intestinal adenocarcinoma cells. METHODS: Cell survival was examined using colony forming assays. Cell cycle distribution before and after treatment was assessed by flow microfluorimetry. Levels of thymidylate synthase (TS) and topoisomerase I (topo I) in untreated and treated cells were determined by immunoblotting. Changes in deoxynucleotide pools were examined by high-performance liquid chromatography. RESULTS: Clonogenic assays revealed that colony formation was decreased by 50% after a 24-h exposure to 8+/-2 nM SN-38 or 12+/-3 microM 5FU, the latter being assayed in the presence of 2 microM FA. When treatment with 5FU/FA was followed by SN-38, the cytotoxicity was similar to that observed with 5FU/FA alone. In contrast, when HCT-8 cells were exposed to both agents simultaneously or to SN-38 followed by 5FU/FA, the cytotoxicity was greater than that of SN-38 or 5FU/FA treatment alone. Investigation of the mechanistic basis for this sequence dependence revealed that SN-38 treatment was associated with a dose- and time-dependent decrease in conversion of [5-3H]-2'-deoxyuridine to [3H]-H2O and thymidylate in intact cells. Immunoblotting failed to reveal any decrease in TS protein that could account for the decreased activity. High-performance liquid chromatography revealed that SN-38 treatment was associated with increased levels of the deoxynucleotide dTTP and decreased levels of dUTP. Flow microfluorimetry revealed that a 24-h treatment wit 10 nM SN-38 resulted in accumulation of HCT-8 cells in late S and G2 phases of the cell cycle, with a further increase in the G2 fraction during the 24 h after SN-38 removal. CONCLUSIONS: These observations are consistent with a model in which SN-38 sequentially induces diminished DNA synthesis, elevated dTTP pools, inhibition of dUMP synthesis and enhanced toxicity of 5FU/FA. Accordingly, sequencing of irinotecan and 5FU/FA might be important in combining these agents into an effective treatment for colorectal cancer.

Adenocarcinoma↗
PubMed1998

Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer.

PURPOSE: This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy. PATIENTS AND METHODS: Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups. RESULTS: Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01). CONCLUSION: There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.

Adenocarcinoma↗
PubMed1998

Irinotecan plus 5-FU and leucovorin in advanced colorectal cancer: North American trials.

But fluorouracil (5-FU) and irinotecan (CPT-11 [Camptosar]) have shown activity in metastatic colorectal cancer and are approved for its treatment in the United States. Preclinical experiments in cell cultures and human tumor xenografts have indicated potential synergy when irinotecan is combined with 5-FU and leucovorin. The synergy appears to be sequence-dependent and is optimal when irinotecan exposure precedes 5-FU exposure by at least 24 hours. Four North American trials have been reported in which the three drugs were used together in either simultaneous, sequential, or alternating schedules. All three schedules showed activity in patients with metastatic colorectal cancer. The concern that diarrhea, which can be a dose-limiting toxicity with both irinotecan and 5-FU, would prevent the two drugs from being combined in reasonable doses has not proven to be a clinical issue. Phase III trials comparing the combination of the three drugs in a variety of schedules against 5-FU plus leucovorin alone are currently under way or in the planning stages.

Antidotes↗
PubMed1998

Phase I study of the duocarmycin semisynthetic derivative KW-2189 given daily for five days every six weeks.

The duocarmycins represent a new group of antitumor antibiotics produced by Streptomyces that bind to the minor groove of DNA. KW-2189 is a water-soluble semisynthetic derivative of duocarmycin B2, with significant activity in murine and human tumor models. We conducted a Phase I trial of KW-2189 in patients who had solid tumors that were refractory to standard chemotherapy or for whom no more effective therapy existed. KW-2189 was administered as a rapid i.v. bolus daily for 5 days every 6 weeks. Twenty-two patients were enrolled and received a total of 31 cycles of KW-2189. Leukopenia, neutropenia, and thrombocytopenia were the dose-limiting toxicities, with nadirs occurring at medians of 36, 38, and 29 days, respectively, at the 0.04 mg/m2/day dose level. Nonhematological toxicities were mild, although one patient developed grade 3 fatigue. Four patients had stable disease over two to four cycles of treatment and showed no cumulative toxicity. The mean t1/2, plasma clearance, and steady-state volume of distribution were 13.5 min, 1,287 ml/min/m2, and 10,638 ml/m2, respectively. Pharmacokinetics were similar on days 1 and 5, with no drug accumulation in plasma. The active metabolite DU-86 was not consistently found in patient plasma. For Phase II trials, when the 5 days every 6 weeks schedule was used, 0.04 mg/m2/day KW-2189 appears to be the maximal tolerated dose, especially for patients who have received prior chemotherapy. At this dose level, the drug was well tolerated, and the toxicities were acceptable.

Adult↗
PubMed1997

Evaluation of continuous infusion suramin in metastatic breast cancer: impact on plasma levels of insulin-like growth factors (IGFs) and IGF-binding proteins.

Suramin represents a new class of antitumor drugs that targets growth factor networks. In this Phase II trial, suramin was administered by continuous infusion to 10 patients with advanced breast cancer. The target level of 280 microgram/ml suramin was achieved in a median of 10 days; toxicities in this patient group were low. We monitored the insulin-like growth factor (IGF) network in these patients because of the previously defined growth-promoting role of the IGFs in breast cancer. Plasma levels of total IGF-I and total IGF-II showed variable responses to suramin with median decreases of 24 and 23%, respectively, for the 10 patients; for total IGF-I levels, this did not reach statistical significance. On the other hand, free IGF-I plasma levels were consistently and dramatically increased (over 250%) after suramin infusion. IGF-binding proteins (IGFBPs), modulators of IGF bioavailability, were also measured. Levels of IGFBP-3, the major carrier of IGFs in the circulation, were decreased 21% after suramin treatment when measured by immunoradiometric assay. However, the majority of the plasma IGFBP-3 remaining after suramin was not the intact high-affinity IGF-binding form but rather a 30-kDa fragment with markedly reduced affinity for IGF-I. IGFBP-3 protease activity was evident in the plasma of 3 of 10 patients after suramin. Measurements of plasma IGFBP-1, IGFBP-2, and IGFBP-4 revealed no significant changes in response to suramin. The dramatic increase in active free IGF-I seen after suramin raises concern and underscores the importance of measuring relevant biomarkers in clinical trials.

Adult↗
PubMed1997

Phase I and pharmacological trial of fazarabine (Ara-AC) with granulocyte colony-stimulating factor.

Fazarabine (1-beta-D-arabinofuranosyl-5-aza-cytosine, or Ara-AC) is a nucleoside analogue that consists of the arabinoside ring of 1-beta-D-arabinofuranosylcytosine and the pyrimidine base of 5-azacytidine. In Phase I and Phase II trials, neutropenia was dose limiting, with minimal nonhematological toxicity. The in vitro cytotoxic concentrations of Ara-AC could not be achieved in these studies; neutropenia precluded dose escalation. The objectives of this study were: to determine either the maximum tolerated dose of Ara-AC or to safely achieve target plasma levels of 2-5 microgram/ml when Ara-AC was administered as a 24-h infusion with granulocyte colony-stimulating factor (G-CSF) to patients with advanced refractory malignancies; to characterize the pharmacokinetic behavior of Ara-AC with G-CSF; and to define the relationship of Ara-AC pharmacokinetics to toxicity. Twenty-four patients received 67 courses of Ara-AC at doses of 54-112 mg/m2/h. Dose-limiting toxicity was approached but not reached. Grade 3 or 4 neutropenia and nausea were the principle side effects. Steady-state plasma concentrations exceeded the minimum target concentration of 2 microgram/ml in all patients who received >/=78 mg/m2/h for 24 h. The maximum target concentration was approached during administration of 112 mg/m2/h for 24 h. The mean steady-state clearance was 475 +/- 103 ml/min/m2 and did not change with dose. One partial response was seen. One patient received 16 courses and another received 7 courses of therapy before progression. Ara-AC can be safely administered in doses that result in plasma concentrations of 2-5 microgram/ml, if it is given with G-CSF. Phase II trials of Ara-AC in selected malignancies are planned.

Adult↗
PubMed1996

A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.

PURPOSE: To evaluate the toxicities of a Phase I study of radiation therapy with concurrent 5-fluorouracil (5FU) and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. METHODS AND MATERIALS: Twenty-seven patients with locally advanced carcinoma of the pancreas (n = 19), bile duct (n = 7), and gall bladder (n = 1) were entered into a Phase I study of combined radiation therapy, 5FU, and folinic acid. Radiation was given as a split course of 40 Gy in 20 daily fractions with a gap of 2 weeks after 20 Gy. 5-Fluorouracil, 300 to 375 mg/m2/day and folinic acid, 20 mg/m2/day were given as an i.v. bolus daily for 5 days beginning on day 1 and again on day 29. RESULTS: Eight patients developed Grade 3 or 4 toxicities (National Cancer Institute common toxicity criteria) including nausea and vomiting (n = 4), oral mucositis (n = 4), myelosuppression (n = 2), infection (n = 2), and diarrhea (n = 1). Four patients did not complete the planned protocol due to treatment toxicities. There were two treatment deaths secondary to septic neutropenia. Treatment toxicity appeared to be related to age (> 70), performance status (ECOG = 2), and 5FU dose (> 350 mg/m2/day). CONCLUSION: This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol.

Adult↗
PubMed1996

Male breast cancer: an 11 year review of 66 patients.

A review was conducted of 66 men with carcinoma of the breast seen at this institution between 1981 and 1992. The results of the study suggest that there are many similarities between breast cancer in men and women. The most common clinical presentation was a lump in the breast. The majority of tumors were T1 or T2, and infiltrating ductal carcinoma was the predominant histological type. Axillary nodal status and histological grade were predictive of survival. The pattern of recurrence and survival rates were similar to those seen in women. Some differences, however, were evident. Tumors were centrally located in the majority of patients and there was a high frequency of nipple involvement. The hormone receptor positivity rate was high and the median age at presentation was older. In comparison to a previous report of the same disease from this institution 10 years ago, fewer patients underwent radical surgical procedures and more patients received adjuvant systemic therapy. These approaches are justified since there are many biological similarities between breast cancer in men and women.

Adult↗
PubMed1996

A phase II trial of 5-fluorouracil and 1-leucovorin in patients with metastatic colorectal cancer.

We undertook a multicenter phase II trial of 5-fluorouracil (5FU) + 1-leucovorin (1-LV) in previously untreated patients with metastatic colorectal cancer to determine the response rate, response duration, time to progression, survival, and toxicity. Patients were treated with i.v. 5FU 370 mg/m2/day and 1-LV 100 mg/m2/day x 5 every 28 days. Toxicity and response were determined by WHO criteria. One hundred and twenty-six patients were entered, and 119 patients were eligible and evaluable. Eighty-eight patients had colon cancer and 37 had rectal cancer. The male:female ratio was 58:68. The mean age was 62.2 years. ECOG performance status distribution was 0 (39.7%), 1 (46%), and 2 (11.9%). The median number of courses of therapy administered was 4.5. Severe- or life-threatening stomatitis or diarrhea, nausea, and granulocytopenia occurred in 17.6, 23.2, 17.6, and 15.9% of patients, respectively. The response rate was 22/119 [18.5%; 95% confidence interval (CI) of 12.0-26.6]. Median response duration was 188 days (95% CI of 111-248 days). Median survival was 379 days (95% confidence interval of 289-452 days). These results indicate that when 1-LV is combined with 5FU, toxicity is similar in pattern and severity to that of the d,1 racemic mixture. The overall efficacy of 1-LV + 5FU is comparable to a recent metaanalysis.

Adult↗
PubMed1995

Biochemical modulation of iododeoxyuridine by N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[cd]indole glucuronate (AG-331) leading to enhanced cytotoxicity.

Inhibition of thymidylate synthase (TS) may increase incorporation of thymidine analogues into DNA, leading to increased inhibition of colony formation in tumor cells. We have reported previously that TS inhibition by N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6,-ylmethyl)-N -methylamino]-2 - thenoyl)-L-glutamic acid (ICI D1694 or Tomudex), a folate-based TS inhibitor, increases the cytotoxicity of iododeoxyuridine (IdUrd), a thymidine analogue, in MGH-U1 human bladder and HCT-8 human colon cancer cells. N6-[4-(Morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]-indole glucuronate (AG-331) differs from ICI D1694 in that it is a de novo designed lipophilic TS inhibitor, it does not require a specific carrier for cellular uptake, and it does not undergo intracellular polyglutamation. Exposure of MGH-U1 cells to 5 microM AG-331 for 24 hr decreased clonogenic survival by 30%, but almost completely inhibited TS activity. IdUrd is a cytotoxic thymidine analogue, with IC50 and IC90 values after 24-hr exposures in MGH-U1 cells of 13 and 81 microM, respectively. The combination of IdUrd and AG-331 resulted in an enhanced antitumor effect, as compared with the effect of either agent alone. The cytotoxic IC50 of IdUrd decreased from 13 to 1.5 microM, and the IC90 decreased from 81 to 5 microM with the addition of 5 microM AG-331. Biochemical studies of the combination revealed that pretreating MGH-U1 cells with 5 microM AG-331 increased IdUrd incorporation into cellular DNA by 3.8-fold. This increased incorporation was associated with a greater proportion of DNA single-strand breaks than observed with either agent alone, and the combination of 5 microM AG-331 plus IdUrd produced up to a 2.5-fold increase in DNA single-strand breaks as compared with IdUrd alone. The effects of AG-331, IdUrd, and the combination of IdUrd and AG-331 on the colony-forming ability of normal human bone marrow CFU-GM cells was determined as a measure of myelosuppression. The combination of IdUrd and AG-331, at the same concentrations as those used in the MGH-U1 cells, produced a wider therapeutic index relative to that of IdUrd alone, and the therapeutic index for the combination was 6.5, as compared with 4.0 for IdUrd plus ICI D1694 in previous studies from this laboratory. These observations suggest that the combination of IdUrd and AG-331 may enhance antitumor effects with minimal myelosuppression in vivo.

Antimetabolites, Antineoplastic↗
PubMed1995

Effects of thymidylate synthase inhibition on thymidine kinase activity and nucleoside transporter expression.

The effects of de novo dTMP inhibition by N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2- thenoyl)-L-glutamic acid (D1694) or N6-[4-(morpholinosulfonyl)benz]-N6-diaminobenz[cd]indole glucuronate (AG-331) on clonogenic survival, thymidylate synthase (TS) and thymidine kinase (TK) activity, and expression of S-(p-nitrobenzyl)-6-thioinosine-sensitive nucleoside transporter (NT) sites were addressed in the human bladder cancer cell line, MGH-U1. These two TS inhibitors are structurally diverse. D1694 is a folate-based TS inhibitor, whereas AG-331 is a novel agent that inhibits the cofactor binding site of the enzyme. They also differ with respect to their cytotoxic effects in this cell line; D1694 cytotoxic 50% inhibitory concentration (IC50) and IC90 were 6.0 and 9.0 nM, respectively and IC50 and IC90 for TS inhibition were 2.5 and 4.8 nM, respectively. In contrast, AG-331 cytotoxic IC50 could not be achieved even at concentrations of up to 20 microM for 24-h exposures, and IC50 and IC90 for TS inhibition were 0.7 and 3.0 microM, respectively. Similar effects for D1694 and AG-331 were observed in their modulation of TK activity and NT expression. 5-(SAENTA-x8)-Fluorescein, a highly modified form of adenosine incorporating a fluorescein molecule which binds with a 1:1 stoichiometry to S-(p-nitrobenzyl)-6-thioinosine-sensitive NT sites, was used to investigate the expression of NT following exposure of cells to D1694 and AG-331. TK activity was addressed by the metabolism of [3H]thymidine to [3H]TMP by cellular extracted protein and by an alternative flow cytometric method using a modified form of thymidine incorporating a fluorescent molecule, dansyl-5-amino-2-deoxyuridine. Results obtained by both methods were comparable. At concentrations of 5 and 10 nM, D1694 increased TK activity 2.3-4.5-fold and NT expression 34-39-fold. AG-331, at concentrations of 5 and 10 microM, increased TK activity 1.8-2.5-fold and NT expression 22-31-fold, respectively. These data suggest that TK activity and NT expression have a common regulatory mechanism which is sensitive to endogenous dTTP pools and that the salvage pathway is a complex system of kinases coordinated with transport of nucleosides.

Carrier Proteins↗
PubMed1995

A clinical and pharmacological study of 5-fluorouracil, leucovorin and interferon alfa in advanced colorectal cancer.

Modulation of 5-fluorouracil (FUra) using leucovorin (LV) is a standard treatment approach in patients with metastatic colorectal cancer. Modulation of FUra with interferon alfa has also shown some promise. Laboratory data have demonstrated increased cytotoxicity when FUra is combined with both LV and interferon. The current study examined the effects of double modulation of FUra using LV and interferon. Patients with measurable advanced colorectal cancer received bolus FUra 375 mg/m2 plus LV 20 mg/m2 daily for 5 days, repeated every 28 days. Recombinant human interferon alfa-2a, 3 million IU/m2 subcutaneously, was given daily on the days of chemotherapy then three times weekly. There was one complete response and nine partial responses (10/41) seen for an overall response rate of 24% (95% CI 12.0-40.0%). Overall, 70% of patients experienced one or more episodes of nonhematologic toxicity of grade 3 or more. Weight loss was common, with a mean decrease of 2.9 kg over the first two months (P < 0.0001). Improvements in tumor-related symptoms were balanced by increased fatigue and a deterioration in body weight and performance status. There was no evidence of progressive changes in FUra metabolism from interferon usage.

Adult↗
PubMed1995

Cytotoxic and biochemical implications of combining AZT and AG-331.

We have reported that noncytotoxic concentrations of 3'-azido-3'-deoxythymidine (AZT) increase the cytotoxicity of ICI D1694, a folate-based thymidylate synthase (TS) inhibitor, with increasing AZT incorporation into DNA. We postulated that the inhibition of TS by ICI D1694 would decrease 5'-deoxythymidine triphosphate (dTTP) pools, which compete with AZT triphosphate (AZT-TP) as a substrate for DNA polymerase. Furthermore, the inhibition of TS would increase the activity of both thymidine kinase (TK) and thymidylate kinase (TdK). Each of these consequences of TS inhibition would favor more incorporation of AZT into DNA. Thus, we reasoned that other TS inhibitors should also result in increased AZT incorporation into DNA and, perhaps, in increased cytotoxicity. N6-[4-(Morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (AG-331) differs from ICI D1694 in that it is a de novo designed lipophilic TS inhibitor, it does not require a specific carrier for cellular uptake, and it does not undergo intracellular polyglutamation. This potent TS inhibitor causes minimal cytotoxicity in MGH-U1 human bladder cancer cells. A 24-h exposure to 5 microM AG-331 causes almost complete TS inhibition but only 35% cell kill. The combination of AZT and AG-331 in MGH-U1 cells resulted in an enhanced antitumor effect relative to that of each agent alone; 50 microM AZT, noncytotoxic alone, increased the cell kill of induced by AG-331 from 35% to 50%. Biochemical studies of this combination revealed that simultaneous treatment with 5 microM AG-331 plus 1.8 microM [3H]-AZT produced as much as a 68% +/- 7% increase in AZT incorporation into DNA. This observation was associated with an increase in DNA single-strand breaks, measured as comet tail moment, of up to 6.6-fold. These studies support our original premise that TS inhibition favors increased incorporation of AZT into DNA and that the combination causes more cell kill than either drug alone in MGH-U1 cells.

Antimetabolites, Antineoplastic↗
PubMed1995

Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis.

Expression of the equilibrative, S-(p-nitrobenzyl)-6-thioinosine (NBMPR)-sensitive nucleoside transporter (es), a component of the nucleoside salvage pathway, was measured during unperturbed growth and following exposure to various antimetabolites at growth-inhibitory concentrations. The probe 5-(SAENTA-x8)-fluorescein is a highly modified form of adenosine incorporating a fluorescein molecule. It binds. with high affinity and specificity to the (es) nucleoside transporter at a 1:1 stoichiometry, allowing reliable estimates of es expression by flow cytometry. Using a dual labelling technique which combined the vital DNA dye Hoechst-33342 and 5-(SAENTA-x8)-fluorescein, we found that surface expression of es approximately doubled between G1 and G2 + M phases of the cell cycle. To address the question of whether es expression could be modulated in cells exposed to drugs which inhibit de novo synthesis of nucleotides, cells were exposed to antimetabolite drugs having different modes of action. Hydroxyurea and 5-fluorouracil (5-FU), which inhibit the de novo synthesis of DNA precursors, produced increases in the expression of es. In contrast, cytosine arabinoside (ara-C) and aphidicolin, which directly inhibit DNA synthesis, produced no significant increase in es expression. Thymidine (TdR), which is an allosteric inhibitor of ribonucleotide reductase that depletes dATP, dCTP and dGTP pools while repleting the dTTP pool, had no significant effect on es expression. These data suggest that surface expression of the es nucleoside transporter is regulated by a mechanism which is sensitive to the supply of deoxynucleotides. Because 5-FU (which specifically depletes dTTP pools) causes a large increase in expression whereas TdR (which depletes all precursors except dTTP) does not, this mechanism might be particularly sensitive to dTTP pools.

Antimetabolites↗