Basis for effective combination cancer chemotherapy with antimetabolites

Peters, Godefridus J.; Wilt, C.L. van der; Moorsel, C.J.A. van; Kroep, Judith R.; Bergman, Andries M.; Ackland, Stephen P.

doi:10.1016/s0163-7258(00)00086-3

Cited by 250 publications

(151 citation statements)

References 116 publications

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“…Such different antitumour mechanisms suggest a potential synergism between 5-FU and gemcitabine. This potential synergism has been indeed observed in in vitro studies using various cancer cell lines (Schulz et al, 1998;Peters et al, 2000).…”

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confidence: 59%

UFT plus gemcitabine combination chemotherapy in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial

et al. 2005

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A multi-institutional phase II trial was conducted to evaluate the efficacy and toxicity of combination chemotherapy consisting of gemcitabine and UFT, which is composed of tegafur and uracil, for non-small-cell lung cancer (NSCLC) patients. Patients with advanced NSCLC received an oral administration of UFT (tegafur 200 mg m À2 ) b.i.d. from days 1 to 14 and intravenous injection of gemcitabine 900 mg m À2 on days 8 and 15. This treatment was repeated every 4 weeks. A total of 44 patients were enrolled into this trial. The median age of all patients was 74 years, with 23 patients younger than 75 years and 21 patients with 75 years of age or older. A total of 18 patients (41%) achieved a partial response. The median survival time was 13.2 months and the 1-year survival rate was 59%. The most common grade 3 -4 toxicity was neutropenia (57%). The frequency of grade 3 nonhaematologic toxicities was less than 5%. In addition, no significant difference in the response, survival or toxicities was observed between the patients younger than and those older than 75 years of age. This combination chemotherapy demonstrated a promising effectiveness and acceptable toxicity in patients with advanced NSCLC, even in patients older than 75 years.

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confidence: 59%

UFT plus gemcitabine combination chemotherapy in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial

et al. 2005

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“…Preclinical studies have shown additive and synergistic effects of gemcitabine and CDDP in combination. Gemcitabine increases the formation of DNAplatinum adducts, while CDDP increases the incorporation of gemcitabine into DNA-platinum adducts (van Moorsel et al, 1999a;Peters et al, 2000). This combination has shown significant activity in a number of tumour types and has become a standard regime in advanced lung cancer (Rinaldi et al, 2000;Sandler et al, 2000).…”

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confidence: 99%

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

Tanaka

Sun

et al. 2005

Br J Cancer

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The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg À1 injection (inj) À1 ) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset -HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg À1 inj À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 inj À1 at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P ¼ 0.001). Gemcitabine -cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (Po0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P ¼ 0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.

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“…On the other hand, previous studies have shown that GEM induces major alterations in the pharmacodynamics, pharmacokinetics, and antitumour activity of 5-FU that may lead to positive antitumour results also in colon carcinoma patients (Berlin et al, 1998(Berlin et al, -1999 A total of 296 chemotherapy cycles were administered (a median range of 10 cycles per patient). Schulz et al, 1998;Correale et al, 1999Correale et al, , 2000aCorreale et al, , b, 2003Poplin et al, 1999;Madajewicz et al, 2000;Peters et al, 2000). In more recent preclinical studies we also found that GEM, used at concentrations potentially achievable in patients, is able to enhance the cytotoxic and proapoptotic activity of oxaliplatin and FUFA combination (Correale et al, 2000a, b, 2002, andunpublished data).…”

Section: Discussionmentioning

confidence: 88%

A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma

Correale

Messinese

Caraglia³

et al. 2004

Br J Cancer

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Previous results suggest that GEM affects 5-fluorouracil (5-FU) metabolism and pharmacokinetics in cancer patients, while combined with oxaliplatin, levo-folinic acid, and 5-FU (GOLF regimen), at doses achievable in cancer patients, determines high cytotoxic and proapoptotic antitumour activity in colon cancer cells in vitro. On these bases we designed a phase I -II clinical trial testing the GOLF regimen in patients with metastatic colorectal carcinoma, who had received at least a prior line of chemotherapy. In total, 29 patients (20 males and nine females) enrolled in the study received every 2 weeks, gemcitabine (patients #1 -3 received 600 mg m À2 ; patients # 4 -6 received 850 mg m À2 ; while patients # 7 -29 received 1000 mg m À2 ) on the day 1, levo-folinic acid (100 mg m À2 ) on the days 1 and 2; 5-fluorouracil (400 mg m À2 ) in bolus injection, followed by a 22-h continuous infusion (800 mg m À2 ) on the days 1 and 2, and oxaliplatin (85 mg m À2 ), 6 h after the 5-FU bolus on day 2. The most frequent side effect was grade I -II haematological toxicity. In total, 28 patients were evaluable for response: three achieved a complete response, nine a partial response, 10 had a stable disease, and six progressed. The average time to progression and overall survival of the patients was, respectively, 7.26 and 22 months. Our GOLF combination is well tolerated and seems promising for the treatment of advanced colorectal cancer.

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Basis for effective combination cancer chemotherapy with antimetabolites

Cited by 250 publications

References 116 publications

UFT plus gemcitabine combination chemotherapy in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial

UFT plus gemcitabine combination chemotherapy in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma

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