Related Experiment Videos
A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity
L R Kelland1, C F Barnard, K J Mellish
1CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, Surrey, United Kingdom.
Abstract:
As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of trans coordination geometry centered on trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335) has been evaluated in vitro against a panel of cisplatin-sensitive and cisplatin-resistant human tumor cell lines (predominantly ovarian). In vitro, against 5 human ovarian carcinoma cell lines, JM335 was comparably cytotoxic to cisplatin itself and over 50-fold more potent than transplatin (mean 50% inhibitory concentrations: JM335, 3.1 microM; cisplatin, 4.1 microM; transplatin, 162 microM). With the use of seven pairs of human tumor cell lines (parent and subline with acquired resistance to cisplatin and encompassing all of the known major mechanisms of resistance to cisplatin) JM335 exhibited a different cross-resistance pattern to that of its cis isomer (JM149). JM335 showed non-cross-resistance in six of the seven resistant lines, cross-resistance in the A2780cisR line possibly being associated with high levels of glutathione. Preliminary intracellular DNA binding studies showed that in contrast to transplatin, JM335 was efficient at forming DNA-DNA interstrand cross-links. In vivo, JM335 produced growth delays in excess of 15 days against 4 of 6 human ovarian carcinoma xenografts and was unique among the complexes studied in retaining some efficacy against a cisplatin-resistant subline of the murine ADJ/PC6 plasmacytoma. JM335 is the first trans-platinum complex to demonstrate marked antitumor efficacy against both murine and human s.c. tumor models and represents a significant structural lead to complexes capable of circumventing cross-resistance to cisplatin.
Insights
A new platinum complex, JM335, shows potent anticancer activity against ovarian cancer cells and overcomes cisplatin resistance. This trans-platinum compound demonstrates significant efficacy in both human and murine tumor models, offering a promising lead for new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Platinum-based drugs are crucial in cancer chemotherapy.
- Cisplatin resistance limits treatment efficacy.
- Development of novel platinum complexes with altered resistance profiles is needed.
Purpose of the Study:
- To evaluate the in vitro and in vivo anticancer activity of trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335).
- To assess JM335's efficacy against cisplatin-sensitive and resistant tumor cell lines.
- To investigate JM335's potential to overcome cisplatin resistance mechanisms.
Main Methods:
- In vitro cytotoxicity assays against human ovarian carcinoma cell lines.
- Cross-resistance studies using cisplatin-resistant and sensitive tumor cell line pairs.
- Intracellular DNA binding studies.
- In vivo efficacy studies using human ovarian carcinoma xenografts and murine tumor models.
Main Results:
- JM335 exhibited comparable cytotoxicity to cisplatin and significantly higher potency than transplatin in vitro.
- JM335 displayed a distinct cross-resistance pattern compared to its cis isomer, overcoming resistance in six of seven tested lines.
- JM335 demonstrated significant antitumor efficacy in vivo, including activity against cisplatin-resistant models.
- JM335 effectively formed DNA-DNA interstrand cross-links.
Conclusions:
- JM335 is a potent trans-platinum complex with significant antitumor activity.
- JM335 shows promise in circumventing cisplatin resistance.
- JM335 represents a valuable structural lead for developing next-generation platinum anticancer drugs.