D-19466, a new cyclobutane-platinum complex with antitumor activity

Voegeli, R.; Schumacher, W; Engel, Jürgen; Respondek, J.; Hilgard, P.

doi:10.1007/bf01612990

Cited by 34 publications

(18 citation statements)

References 3 publications

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“…One of these compounds might be lobaplatin (1,2-diamminomethylcyclobutane-platinum (II)-lactate, D-19466) (Figure 1). Lobaplatin has a greater anti-tumour effect in vitro towards B16 melanoma and AH13s hepatoma than cisplatin (Voegeli et al, 1990). This was also implied by experiments performed in two cell lines and their cisplatin-resistant sublines.…”

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confidence: 74%

“…In vivo, in mice bearing P388 leukaemia, administration of lobaplatin resulted in a greater increase in lifespan than cisplatin or carboplatin. In a cisplatin-resistant P388 tumour in which neither cisplatin nor carboplatin was able to inhibit the proliferation after transplantation, the survival of the animals was significantly prolonged by lobaplatin (Voegeli et al, 1990). These preclinical in vitro and animal data suggest that the anti-tumour activity of lobaplatin is different from that of cisplatin and carboplatin and might be not cross-resistant.…”

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confidence: 89%

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Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer

Gietema

Veldhuis²,

Guchelaar³

et al. 1995

Br J Cancer

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Summary In phase I studies. lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mgm-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3 4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P<0.0l). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 ± 0.5, 3.0 ± 0.6. and 3.2 ± 1.1 h mgl-' for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 ± 5% and 24 h after infusion 74 ± 3% of the lobaplatin dose was excreted in the urine. In conclusion. lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.Keyword: ovarian cancer; phase II; lobaplatin Over the last decade, treatment of patients with ovarian cancer has been dominated by cisplatin-containing regimens (Neijt et al., 1984;Williams et al., 1985; Omura et al., 1986). Combinations of cisplatin with one single alkylating agent give equivalent results to three-or four-drug schedules, but appear to be less toxic (Neijt et al., 1987). In recent years, the development of new drugs has been directed towards the development of platinum analogues that are equipotent but less toxic than the parent compound. Carboplatin has emerged as leading analogue in this respe-t with reduced nephrotoxicity, gastointestinal toxicity and neurotoxicity (Calvert et al., 1982;Evans et al., 1983). Myelotoxicity, especially thrombocytopenia. has been found to be the doselimiting toxicity of carboplatin. Especially in ovarian cancer, carboplatin appears to have equivalent activity to cisplatin (Alberts et al., 1992;Swenerton et al., 1992).An important direction in current r...

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mentioning

confidence: 74%

mentioning

confidence: 89%

Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer

Gietema

Veldhuis²,

Guchelaar³

et al. 1995

Br J Cancer

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“…The preclinical data suggest that the anti-tumour activity of lobaplatin is different from that of cisplatin and carboplatin and might be not cross-resistant (Harstrick et al, 1994;Voegeli et al, 1990;McKeage et al, 2001). Clinically, lobaplatin is tolerable at recommended dosages.…”

Section: Preclinical Activity Of Lobaplatin As a Single Agent And In mentioning

confidence: 99%

Preclinical Activity of Lobaplatin as a Single Agent and in Combination with Taxanes for Ovarian Carcinoma Cells

Sun¹,

Lou²,

Sui³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Lobaplatin, one of the third -generation platinum compounds, has shown encouraging anticancer activity in a variety of tumor types. However, the efficacy of lobaplatin in ovarian cancer has not been systemically evaluated. In this study, lobaplatin as a single agent and in combination with taxanes was investigated in -vitro and in an in vitro model of ovarian carcinoma. Using the sulforhodamine B (SRB) assay, the cytotoxic effects of lobaplatin alone and in combination with taxanes were compared with cisplatin and carboplatin in seven ovarian cancer cell lines. In addition, in -vitro antitumor activities were evaluated with cisplatin -sensitive and cisplatin -resistant human ovarian cancer xenografts in nude mice. The cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with IC 50 values from 0.9 to 13.8 µmol/L in a variety of ovarian cancer cells. The combination of lobaplatin with docetaxel yielded enhanced cytotoxic activity in vitro. In addition, in platinum -sensitive ovarian cancer xenografts, lobaplatin alone showed similar antitumor activity to cisplatin and carboplatin. Furthermore, lobaplatin alone or in combination with docetaxel exhibited significant activity in platinum -resistant ovarian cancer xenografts. These results indicate that the use of lobaplatin alone or in combination with docetaxel might be a rational and novel therapeutic strategy for ovarian cancer. Further clinical development of lobaplatin is clearly warranted.

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“…Third generation platinum analogues that might be an alternative for the treatment of CDDP refractory tumours are for instance lobaplatin (D19466, 1,2-bisamminomethylcyclobutaneplatinum(II)-lactate) and enloplatin (CL 287,110; (SP-4-2)-[1,1-cyclobutanedicarboxylato (2)-O,O'] (tetrahydro-4H-pyran-4,4-dimethanamine-N,N') platinum). For lobaplatin only partial cross resistance was found in a CDDP resistant murine leukaemia cell line (Voegeli et al, 1990). In our laboratory we observed cross resistance for lobaplatin in GLC4-CDDP, but none in a CDDP resistant teratocarcinoma cell line (Meijer et al, 1991).…”

Section: Cddp Analoguesmentioning

confidence: 99%

Modulation of cis-diamminedichloroplatinum(II) resistance: a review

Timmer‐Bosscha

Mulder²,

Vries³

1992

Br J Cancer

148

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Summary In this review an inventory is made of agents used to circumvent cis-diamminedichloroplatinum(II) (CDDP) resistance in vitro and in vivo. Agents that affect CDDP accumulation and membrane related systems, cytoplasmic defense mechanisms, as well as DNA accessibility and repair are reviewed.In resistant cell lines that have decreased accumulation, this can be restored by hyperthermic treatment. With or without effects on accumulation compounds that affect cell signal transduction often increase CDDP cytotoxicity. Calcium channel blockers and calmodulin inhibitors do not seem to be uniformly good modulators of CDDP resistance. For transduction modulators as well as cellular calcium affecting agents mechanisms are mainly unclear or controversial. Glutathione appears, with the now available agents, to be the most promising target for modulation of cytoplasmic defense mechanisms. At the nuclear level the inhibition of DNA repair related enzymes as well as the use of modified nucleosides to interfere with repair is studied in various cell lines. Results with these agents suggest opportunities for clinically feasible cytotoxicity modulation. DNA accessibility could in vitro be affected, but seems to be an unreliable target for modulation. Whenever possible the resistance mechanism affected and the mode of action of the modulator are discussed. As an alternative for modulation another method of overcoming CDDP resistance namely the application of CDDP analogues is considered.

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D-19466, a new cyclobutane-platinum complex with antitumor activity

Cited by 34 publications

References 3 publications

Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer

Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer

Preclinical Activity of Lobaplatin as a Single Agent and in Combination with Taxanes for Ovarian Carcinoma Cells

Modulation of cis-diamminedichloroplatinum(II) resistance: a review

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