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Biomedical subjects

C Erlichman

Publications and source records attributed to C Erlichman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Differences between accumulation of 99mTc-MIBI and 201Tl-thallous chloride in tumour cells: role of P-glycoprotein.

Both 99mTc-MIBI and 201Tl have been used for tumour imaging. It has recently been reported that 99mTc-MIBI is a substrate for P-glycoprotein (Pgp), a membrane pump which mediates multidrug resistance. We have evaluated the role of Pgp in the cellular accumulation of 201Tl by using sensitive and resistant strains of Chinese hamster ovary (CHO) fibroblasts (AuxB1 and CHRC5, respectively) grown in suspension culture. 201Tl accumulation was the same in sensitive and resistant cells, whereas 99mTc-MIBI accumulation was much lower in resistant cells than in sensitive ones. Down-modulation of Pgp with 100 microM verapamil did not alter cellular accumulation of 201Tl while it significantly increased 99mTc-MIBI accumulation in both types of cell. Similarly, 10 microM verapamil did not affect the rate of washout of 201Tl from preloaded cells, while 99mTc-MIBI washout was greatly reduced in the presence of verapamil. These results suggest that 201Tl will accumulate in both sensitive and resistant tumour cells, whereas 99mTc-MIBI will be extruded from resistant cells and therefore may be less useful for tumour detection when the tumour cells express high Pgp levels.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

ICI D1694 and idoxuridine: a synergistic antitumor combination.

The cytotoxicity of idoxuridine (IdUrd), a thymidine analogue, and ICI D1694 (D1694), a folate-based thymidylate synthase (TS) inhibitor, were examined individually and in combination in two human tumor cell lines. MGH-U1 bladder cancer and HCT-8 colon cancer cells were grown as monolayer cultures with and without thymidine. The cytotoxicity of these agents alone and in combination were determined using normal human bone marrow colony-forming unit, granulocyte-macrophage (CFU-GM) as a surrogate for myelosuppression in vivo. Thymidylate synthase inhibition, IdUrd incorporation into DNA, and DNA single-strand breaks were measured in each cell line and related to cytotoxicity. The cytotoxicity of a 24-h exposure to IdUrd or D1694 increased with drug concentration in each cell line. The drug concentrations producing 50% and 10% clonogenic survival in MGH-U1 cells, respectively, were 0.006 and 0.009 microM for D1694 and 13.0 and 81.0 microM for IdUrd. Those for HCT-8 cells, respectively, were 0.009 and 0.018 microM for D1694 and 7.5 and 20.5 microM for IdUrd. The cytotoxicity of IdUrd combined with D1694 was synergistic in both MGH-U1 and HCT-8 cells as determined by median-effect analysis. The addition of thymidine at concentrations of 0.1, 0.3, and 1.0 microM to the culture medium did not decrease the cytotoxicity of D1694 in either tumor cell line. TS inhibition using the whole cell assay was observed with only D1694, producing 50% inhibition of TS activity at 0.002 microM for MGH-U1 and 0.007 microM for HCT-8 cells. IdUrd did not inhibit TS activity, nor did it enhance the TS inhibitory effects of D1694. The incorporation of IdUrd into DNA increased with increasing concentrations of D1694. This increased DNA incorporation correlated with the increase in DNA single-strand breaks. DNA single-strand breaks paralleled cytotoxicity. CFU-GM survival, exposed to the same drug concentrations as those used in the tumor cell lines, revealed that the therapeutic index was greater for the combination than for either agent alone. These findings suggest that IdUrd plus D1694 is a promising new drug combination, which may have a favorable therapeutic index in vivo.

Antimetabolites, Antineoplastic↗
PubMed1994

Phase II trial of 5-fluorouracil and folinic acid in the treatment of advanced breast cancer.

Standard combination chemotherapy for metastatic breast cancer produces response rates between 30-60% with limited impact on survival. We undertook a phase II trial to determine the activity of 5 fluorouracil (5FU) and folinic acid (FA) in patients with measurable metastatic or recurrent breast cancer who had received no prior chemotherapy. Patients meeting the eligibility criteria received 5FU 370 mg/m2/day and FA 200 mg/m2/day for 5 days repeated every 28 days, toxicity allowing. Response defined by standard criteria was assessed every 8 weeks and toxicity according to WHO criteria was determined on every course. Thirty-three patients were entered on trial. Thirty-two patients were evaluable for response and 33 for toxicity. The dose limiting toxicity was stomatitis with 7/32, 19/32, and 5/32 patients experiencing grade 1, 2, and 3 toxicity. Grades 1 and 2 diarrhea occurred in 17/32 and 11/32 patients respectively. Myelosuppression was not significant. Two complete and 11 partial responses were observed. The overall response rate was 41% (95% CI, 24-58%). Responses were seen in soft tissue and visceral sites. Patients who had received adjuvant chemotherapy more than 6 months prior to receiving 5FU and FA responded also. Six of 29 patients receiving standard combination chemotherapy as second line treatment responded subsequently. We concluded: 1) 5FU and FA is an active combination in the treatment of breast cancer warranting further evaluation in combination with other drugs; 2) the dose-limiting toxicity of stomatitis is tolerable; 3) patients receiving 5FU and FA as first line therapy can respond to conventional combination chemotherapy as second line treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Comparative cytotoxicity of folate-based inhibitors of thymidylate synthase and 5-fluorouracil +/- leucovorin in MGH-U1 cells.

Thymidylate synthase (TS) is a critical enzyme in the synthesis of DNA and an important target for cancer chemotherapy. 5-Fluorouracil (5FU) combined with leucovorin (LV) has been used to inhibit TS, and inhibition is dependent on the formation of a ternary complex between a folate cofactor, TS, and 5-fluorodeoxyuridine monophosphate (FdUMP), a metabolite of FU. The folate-based TS inhibitors CB3717, its analogs, and BW1843U89 have been synthesized as specific inhibitors of TS that do not require activation or the presence of a cofactor. We have compared the cytotoxicity of 5FU +/- LV with that of these folate-based TS inhibitors in human bladder cancer MGH-U1 cells using a colony-forming assay. After a 6-h exposure, FU+LV, CB3717, dCB3717, or C2 methyl dideazafolate analogs demonstrated similar cytotoxic potency that was 0.96 to 2.9 times that of 5FU alone. A 24-h exposure did not increase the potency of 5FU+LV relative to 5FU alone, but there was a marked increase in the cytotoxicity of the dideazafolates as compared with 5FU+LV. Similarly, BW1843U89 was more cytotoxic than 5FU/LV. This was reflected in a 3.2- to 1333-fold decrease in the 50% inhibitory concentration (IC50). Simultaneous exposure to LV and thymidine (TdR) protected MGH-U1 cells from the cytotoxicity of CB3717, its analogs, and BW1843U89. We conclude that (a) the folate-based TS inhibitors are more potent than 5FU+LV after a 24-h exposure, (b) protection by LV and TdR indicates that TS inhibition is the primary site of action, and (c) BW1843U89 is more potent than D1694 in MGH-U1 cells.

Antineoplastic Agents↗
PubMed1994

Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer.

A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3-4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses of subsequent courses could be determined.

Adult↗
PubMed1994

Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells.

The TS-inhibitory effects induced by a 24-h exposure to the folate-based TS inhibitors CB3717, C2-desamino analogs of CB3717 including D1694, and BW1843U89 were quantitated using the MGH-U1 human bladder carcinoma. The effects of D1694 on the time course of TS inhibition and on intracellular deoxyuridine monophosphate (dUMP) accumulation and deoxyuridine (dUrd) production were evaluated. D1694 and BW1843U89 were the most active TS inhibitors with IC50 values of 2.4 and 0.5 nM, respectively. The C2-desamino C2-methyl dideazafolates were 27-292 times more potent than the parent CB3717 as TS inhibitors. A methyl group at the C2 position of CB3717 had the most dramatic effect, whereas a thiazole substitution for a benzyl added a small benefit and N10 substitution had a limited impact on TS-inhibitory potency and clonogenic survival. There was a significant correlation between the IC50 values for TS inhibition and those for cytotoxic potency obtained for these drugs. LV and thymidine protected cells from these folate-based TS inhibitors. Intracellular dUMP levels following 24 h D1694 (IC50) exposure increased 7-fold. Levels of dUrd effluxing into the media increased up to 4.5 microM following a 24-h exposure to D1694 (IC90). We conclude that (a) C2-desamino C2-methyl dideazafolates are potent TS inhibitors, (b) TS inhibition requires prolonged exposure with these folate TS inhibitors, (c) survival is correlated with inhibition of TS for the folate-based TS inhibitors and (d) the biochemical consequences of TS inhibition include increased dUMP and dUrd levels.

Cell Survival↗
PubMed1994

Necrosis in a meningioma following systemic chemotherapy. Case report.

Radiological and clinical evidence of acute necrosis in a meningioma following one cycle of chemotherapy with 5-fluorouracil, folinic acid, and levamisole was observed in a patient being treated for invasive rectal carcinoma. The possible mechanisms and implications of this occurrence are discussed.

Adenocarcinoma↗
PubMed1993

Combination studies with 3'-azido-3'-deoxythymidine (AZT) plus ICI D1694. Cytotoxic and biochemical effects.

The cytotoxicity of 3'-azido-3'-deoxythymidine (AZT), a thymidine analogue, and ICI D1694, a folate-based thymidylate synthase (TS) inhibitor, was examined individually and in combination in two human tumor cell lines, MGH-U1 bladder cancer and HCT-8 colon cancer cells, grown as a monolayer culture with and without thymidine (TdR). In addition, TS inhibition, [3H]AZT incorporation into DNA, [3H]AZT-MP (monophosphate) production, and DNA double-strand breaks were measured. Twenty-four hour exposure of AZT at 0.5, 5, 50 and 500 microM was not cytotoxic to MGH-U1 or HCT-8 cells in a colony-forming assay. ICI D1694 cytotoxicity increased with drug concentration, and the IC50 and IC90, respectively, were 0.0064 and 0.01 microM in MGH-U1 cells and 0.009 and 0.018 microM in HCT-8 cells. TdR in concentrations of 0.1 to 1.0 microM did not affect ICI D1694 cytotoxicity in either cell line. AZT at 5, 50 or 500 microM increased ICI D1694 cell kill. The IC50 and IC90 for MGH-U1 were 0.0037 and 0.0075 microM for 50 microM AZT combined with ICI D1694. The IC50 and IC90 for HCT-8 were 0.0075 and 0.015 microM for 50 microM AZT plus ICI D1694. The incorporation of [3H]AZT into DNA increased with increasing concentrations of ICI D1694. Concentrations producing an IC50 and IC90 of ICI D1694, respectively, increased incorporation of [3H]AZT into DNA by 319 and 569% in MHG-U1, and 243 and 400% in HCT-8 cells. The formation of [3H]AZT-MP paralleled the increase in [3H]AZT incorporated into DNA. AZT, ICI D1694 and the combination of AZT and ICI D1694 caused DNA double-strand breaks, with the combination of these agents being additive. CFU-GM survival, exposed to drug concentrations, as those used in the tumor cell lines, revealed that the therapeutic index was greater for AZT plus ICI D1694 than for ICI D1694 alone. These findings suggest that AZT plus ICI D1694 may increase antitumor effect with minimal myelosuppression. We conclude that AZT increases the cytotoxicity of ICI D1694 with increasing AZT incorporation into DNA.

Colony-Forming Units Assay↗
PubMed1993

Phase I pharmacokinetic study of cyclosporin A combined with doxorubicin.

We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 micrograms/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 micrograms/kg/min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 mumol/liter at the initiation of the infusion to a median of 40.4 mumol/liter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body clearance of 0.177 liter/h/kg. The area under the concentration x time curve (AUC) increased linearly with dose of dox, and total body clearance was independent of dose. The mean total body clearance was 2.46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and/or excretion of dox or increased bone marrow stem cell sensitivity to dox.

Adult↗
PubMed1993

A phase II study of 5-fluorouracil, leucovorin and interferon-alpha in advanced pancreatic cancer.

Increased activity against colorectal cancer by 5-fluorouracil (5-Fu) modulation with leucovorin (LV) and/or interferon (IFN) has been reported. In this study 22 patients with measurable advanced pancreatic cancer received 5-Fu 375 mg/m2 and LV 20 mg/m2 by i.v. bolus daily x 5 every 28 days plus IFN-alpha 3 million units/m2 s.c. There were three out of 21 (14%) responses lasting from 4 to 8 months. Sixteen patients (73%) had one or more episodes of grade 3 or greater toxicity (stomatitis, diarrhea or fatigue). While this combination has some activity against pancreatic cancer, its toxicity limits its potential as a palliative treatment.

Adenocarcinoma↗
PubMed1992

Biochemical modulation of 5-fluorouracil with or without leucovorin by a low dose of brequinar in MGH-U1 cells.

Combination of low doses of de novo pyrimidine biosynthesis inhibitors with 5-fluorouracil (FU) has been proposed to increase the antitumor activity of FU. Brequinar is such an inhibitor that has little clinical anti-tumor effect when used alone. We determined the clonogenic survival of MGH-U1 cells treated with FU +/- leucovorin (LV) +/- brequinar and examined the effects of these treatments on thymidylate synthase (TS). After 24 h exposure, the concentrations resulting in 50% inhibition of cell growth (IC50) for brequinar, FU, and FU+LV (100 microM) were 0.4, 20, and 10 microM, respectively. Both 24 h pretreatment and 48 h continuous treatment with the IC10 (0.1 microM) of brequinar increased the cytotoxicity of FU but did not enhance that of FU+LV. Simultaneous 24 h exposure to 0.1 microM brequinar and FU +/- LV did not increase the cytotoxicity of FU +/- LV. Intracellular cytidine triphosphate (CTP) and uridine triphosphate (UTP) pools, free TS binding sites, and levels of free fluorodeoxyuridine monophosphate (FdUMP) and deoxyuridine monophosphate (dUMP) were measured in cells pretreated with 0.1 microM brequinar for 24 h alone or followed by a 2-h exposure to FU (25 microM) +/- LV (100 microM). In brequinar-treated cells, CTP and UTP pools amounted to 68% and 46% of control values, respectively. The free TS binding sites remaining amounted to 70% of control values in cells treated with FU and 9% of control levels in those treated with FU+brequinar. Free FdUMP levels increased 5-fold in cells pretreated with brequinar as compared with those treated with FU alone. The increased formation of FdUMP was inhibited by simultaneous exposure to 100 microM hypoxanthine and 25 microM FU. Intracellular dUMP levels were not affected by brequinar. We conclude that a low dose of brequinar increases the cytotoxicity of FU but does not enhance that of FU+LV when exposure to brequinar precedes FU treatment. This potentiation appears to be mediated by the increased formation of FdUMP as a consequence of an increase in the cosubstrate phosphoribosyl pyrophosphate (PRPP).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Prognostic factors in patients with metastatic colorectal cancer receiving 5-fluorouracil and folinic acid.

We have reported that 5-fluorouracil (5-FU) and folinic acid increased response rate and survival in patients with metastatic colorectal cancer. Now we have analysed prognostic factors for response, toxicity, survival and time to progression. The variables used for survival and response were treatment centre, treatment, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), site of disease, previous radiotherapy, site of primary, disease-free interval, initial alkaline phosphatase (AP), albumin (A), lactate dehydrogenase (LDH) and aspartate aminotransferase (SGOT). The significant independent variables for survival were PS of 2 or more, initial albumin and SGOT, and treatment received, in order of importance. The relative risk of death when patients received 5-FU/folinic acid was 60% of that of patients receiving 5-FU alone. The variables predictive of response were treatment and PS. The variables used for analysis of toxicity were age, treatment centre, treatment, sex, tumour response, PS, number of courses, SGOT, AP and albumin. Treatment was found to be predictive of toxicity. Thus, baseline albumin and SGOT, and 5-FU/folinic acid treatment are significant determinants of survival, 5-FU/folinic acid and PS of 2 or more are major determinants of response and no clinical parameter could be identified as a predictor of toxicity.

Adult↗
PubMed1991

Phase I pharmacokinetic and pharmacodynamic study of a new anthrapyrazole, CI-937 (DUP937).

We performed a phase I trial of CI-937 (DUP937), an anthrapyrazole, with the following objectives: (a) to determine the maximally tolerated dose in humans; (b) to define the toxicity spectrum of this agent; (c) to describe the pharmacokinetics of the drug; (d) to test a pharmacokinetics based hypothesis of dose escalation; and (e) to relate drug pharmacokinetics to pharmacodynamics. CI-937 was administered as a single bolus injection every 3-4 weeks at doses ranging from 3.6 to 25.2 mg/m2. Thirty-two patients and 57 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 30 patients on the first course using a sensitive and selective radioimmunoassay. The maximally tolerated dose in patients with no prior therapy was 25.2 mg/m2 and dose-limiting toxicity was neutropenia. Thrombocytopenia, nausea, vomiting, stomatitis, and alopecia were mild. A partial response was recorded in a patient with mesothelioma. The area under the curve increased linearly with dose, and total body clearance of CI-937 was independent of dose. The mean total body clearance was 107 +/- 55.8 ml/min/m2, mean steady state volume of distribution was 492 +/- 469 liters/m2, and terminal half-life was 3.78 +/- 2.86 days. The extended factors of 2 methods of pharmacologically guided dose escalation were intended for use but ultimately were equivalent to that of the modified Fibonacci dose escalation method. Dose and the area under the curve were significant predictors of a percentage change in WBC and neutrophil count in a univariate analysis. Only dose and baseline neutrophil count predicted a percentage change in WBCs in a multifactor analysis. Dose and prior chemotherapy predicted percentage change in neutrophil count in a multifactor analysis. We conclude that the dose-limiting toxicity of CI-937 is neutropenia and that the recommended phase II starting dose is 22 mg/m2.

Adult↗
PubMed1991

Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis.

Trials of selective 5-hydroxytryptamine3 receptor antagonists have shown excellent antiemetic activity for chemotherapy containing cisplatin when compared with high-dose metoclopramide. There is little information about the efficacy of these new agents for chemotherapy other than for high-dose cisplatin. We performed a double-blind, randomized trial comparing a single dose of the 5-hydroxytryptamine3 receptor antagonist granisetron (BRL 43694A) as a single intravenous dose with dexamethasone plus prochlorperazine in 152 patients receiving their first course of moderately emetogenic chemotherapy (mainly doxorubicin- and cyclophosphamide-containing combinations). During the first 24 hours, there was a statistically significant advantage for the granisetron group in terms of the prevention of both nausea and emesis. There was no difference in the frequency of reported adverse events. We conclude that granisetron is more effective than dexamethasone plus prochlorperazine in patients who are receiving moderately emetogenic cytotoxic agents.

Antiemetics↗
PubMed1991

Levamisole and 5-fluorouracil therapy for resected colon cancer: a new indication.

OBJECTIVE: To evaluate the benefits and risks of postoperative treatment with levamisole plus 5-fluorouracil (5-FU) in patients with colon cancer. DESIGN: Computerized searches of MEDLINE and CANCERLIT were performed, and the reference list of each retrieved article was checked. Only randomized trials of therapy with levamisole alone or combined with 5-FU for colon cancer without distant metastases were included. The studies were then evaluated with the use of four criteria. RESULTS: We reviewed six randomized trials, of which three satisfied our criteria. Two studies demonstrated a significant improvement in the survival rate with levamisole plus 5-FU among patients with colon cancer and pathologically confirmed metastases to adjacent lymph nodes (Dukes' stage C). A subgroup analysis in another study demonstrated a similar benefit. The toxic effects of the drugs were generally mild. The three other studies showed no difference in survival rates between the treatment groups; however, the samples were too small to detect a clinically or statistically important difference. CONCLUSIONS: Because many patients with colon cancer will suffer a relapse we recommend that they be offered the opportunity to participate in clinical trials of adjuvant therapy. For those with stage C disease not entering a clinical trial levamisole plus 5-FU is appropriate adjuvant therapy.

Colonic Neoplasms↗
PubMed1991

Patients' willingness to enter clinical trials: measuring the association with perceived benefit and preference for decision participation.

Patients who agree and those who refuse clinical trial entry may differ in attitudes towards decision control and the benefits associated with the trial arms. These differences, if they exist, have implications for the process of obtaining informed consent and for the generalization of the results of a clinical trial. This paper describes the development and initial application of methods designed to detect such differences. Developmental work involved creating an inventory of instruments designed to determine patients' attitudes towards participating in treatment decision making, permitting random selection of treatment, and undertaking the risks and benefits associated with the various treatments in a trial. Initial application involved modifying these instruments in terms of an actual chemotherapeutic trial for colonic adenocarcinoma, seeking responses to these measures from 60 non-eligible colorectal cancer patients, then determining whether those who would agree to trial entry differed systematically on these measures from those who indicated that they would refuse such a trial. Twenty-five of the respondents reported that, if faced with the actual decision, they would agree to trial entry: 35 would refuse. Refusers demanded more participation in decision making (Chi-square; P = 0.01) and a greater increment in treatment benefit (t-test; P = 0.0001). Twenty-two of the 35 refusers reported aversion to randomization as their primary reason for trial refusal. Since their particular content can be modified, these measures may be applicable to all clinical trials. They could be used to study the reasons patients accept or refuse trial entry and to determine if agreer-refuser attitude differences undermine the generalizability of a trials results.

Clinical Trials as Topic↗
PubMed1991

Novel chemotherapeutic agents in clinical development.

The development of new chemotherapeutic agents for cancer treatment is pursued with the hope of finding compounds with novel chemical characteristics, unique mechanisms of action, and with improved therapeutic indexes. Seven novel agents at different stages of clinical development have been selected for review. D1694 is a thymidylate synthase inhibitor that has intriguing preclinical activity. The anthrapyrazoles consist of three analogues that are undergoing phase II testing at present. One of these agents, CI-941, has been reported to have significant clinical activity in breast cancer. Lometrexol is an inhibitor of glycinamide ribonuclide transformylase, a critical enzyme in purine biosynthesis, that is undergoing phase II testing. Taxotere, a semisynthetic analogue of taxol that stabilizes microtubules, is currently undergoing phase I testing. Gemcitabine, a fluorinated analogue of deoxycytidine that can inhibit ribonucleotide reductase and be incorporated into DNA, is undergoing phase II testing. BMY-25067 is a mitomycin C analogue that is less myelosuppressive and more active than mitomycin C in preclinical models. Topotecan, a topoisomerase I inhibitor, has been shown to cause myelosuppression as the dose-limiting toxicity in phase I testing. Although each of these agents have some unique and novel characteristics that merit their clinical testing, these agents' long-range clinical role will depend on their efficacy in randomized phase III comparative trials.

Antimetabolites, Antineoplastic↗