Camptothecin sodium

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Representatives of another important class of plant-derived semisynthetic compounds are the camptothecin (27) derivatives, irinotecan (28) and topotecan (29). Camptothecin (27) was originally discovered as an antileukemic agent in a mouse model when isolated from Camptotheca acuminata Decne. Compounds (28) and (29) are both employed in cancer chemotherapy. These substances are important mechanistically because of their activity against the enzyme, topoisomerase I. These compounds were designed to address efficacy and toxicity concerns with the parent compound, camptothecin, and its sodium salt. ... 

Camptothecin is a plant alkaloid obtained from the Camptotheca acuminata tree. It was first evaluated clinically, as a sodium salt, in the 1960s and 1970s, but was abandoned because of severe and unpredictable hemorrhagic cystitis (3,4). Irinotecan (CPT-11) and Rubetecan are semisynthetic, water-soluble derivatives of camptothecin possessing... 

However, the high clinical expectations for camptothecin turned to disappointment in the 1970s because in some clinical studies no effect was observed. So the compound disappeared from the scene. Later, the reason for that failure was discovered. Instead of compound 1, which has a very poor water solubility, the water-soluble sodium salt 2 was used in these early clinical... 

Synthetic approaches to the camptothecin ring system have been published recently for toxic effects of the camptothecin sodium salt see ref. 122. Clinical trials with (66)-Na salt have already been undertaken. Twelve patients with refractory metastatic solid tumours received 20 trials with this compound at 0.5—10.0 mg kg i.v. In five patients there was more than 50 % tumour reduction and improved liver functions in three others duration of response was brief (about 6 weeks). Toxicity effects consisted of alopecia (33%), vomiting (33%), and cystitis (8 %). The drug was relatively well tolerated at 7.5 mg kg every two weeks or at 10 mg kg every three weeks. ... 

Initially incorporated into EVAc polymers, sodium camp-tothecin demonstrated sustained release by in vitro kinetics experiments. Efficacy studies in the established rat intracranial 9L ghosarcoma model showed dramatically increased median survival from 19 days in control animals to > 120 days with 50% (w/w) polymer administration (p< 0.001). Additionally, 59% of treatment animals survived > 120 days no control rats lived beyond 32 days. Systemic camptothecin, in contrast, conferred no survival benefit. Animals undergoing polymer implantation suffered no associated local or systemic toxicity. 

Weingart JD, Thompson RC, Tyler B, Colvin OM, Brem H. Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosar-coma model. Int J Cancer 1995 62 605-609. 

More recently, camptothecin (CPT) was conjugated to poly(l-hydroxymethylethylene hydroxymethylformyl) (PHF or Eleximer ) and the conjugate 11 (XMT-1001) is currently in clinical development [72,73]. The polyacetal is derived from the exhaustive oxidation of dextran [74]. CPT is poorly soluble and prone to rapid inactivation through lactone ring hydrolysis in vivo [75]. As a cytotoxic compound, CPT has been used in many efforts to develop other CPT-polymer conjugates [45,76,77]. The sodium salt of CPT has also been examined in phase I trials, but only modest responses were observed while severe toxicities remain. 

In the late 1960 s, demonstration of the impressive activity of camptothecin opened the door to clinical investigations. Clinical studies were initiated with the sodium salt of camptothecin (2) because of the lack of water-solubility of the parent compound. However, these studies were discontinued owing to the unpredictable occurrence of myelosuppression and severe haemorrhagic cystitis [6-9], in spite of the fact that promising antitumour responses were observed among patients with gastric and colon cancer. The discontinuation of these early clinical studies slowed down the progress of camptothecin research. 

Danishefsky etal. [61] reported an improved route to (20/ .J)-camptothe-cin in connection with their original total synthesis [60, 62-64], Reaction of tricyclic compound (14) with sodium hexamethyldisilazide and benzalde-hyde afforded a 90% yield of the benzylidene acid (15). A mechanism similar to a Stobbe condensation with participation of the methoxycarbonyl function on the pyridone ring is suggested for this reaction step. Ozonolysis of this compound (15) Scheme 2.2) afforded a 96% yield of the acid (16) which, upon esterification, provided (17) in 81% yield. Compound (17) is readily converted to (20/ S)-camptothecin. 

CamptotheCin forms a sodium salt, in which the lactone ring is open, active against L 1210 when administered orally, and this has been used for pre-clinical pharmacology [120, 121]. In Swiss mice, the LD50 value for a single dose is 26-9 mg/kg for oral administration and 57-2 mg/kg for i.v. injection. The maximum tolerated doses by i.v. injections in beagles have been found to be 40 mg/kg for a single dose, 156 mg/kg for daily doses on... 

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