Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid.

Several folate-drug conjugates are currently undergoing clinical trials for application in oncology. However, the efficacy of folate-targeted therapy strongly depends on the folate receptor (FR) abundance at the surface of cancer cells. Recently, it has been postulated that up-regulation of FRα by means of chemo-sensitizing agents could enhance the anticancer activity of FR-drug conjugates. In this study, we demonstrate in vitro that a combination of dexamethasone (Dexa) and valproic acid (VPA) increases FRα expression selectively at the surface of FR-overexpressing cancer cells. The same stimulation was observed in vivo in KB-tumor xenografts when mice are treated with this combined treatment. This effect is reversible since treatment interruption induces the return of FR expression at basal level. When incubated with Dexa and VPA, the ß-galactosidase-responsive folate-monomethyl auristatin E (MMAE) conjugate, called MGAF, exhibits higher cytotoxic activity on several FR-positive human cancer cell lines, compared to its administration as a single agent. This improved toxicity results from the enhanced concentration of MMAE released within cancer cells after internalization and subsequent enzymatic activation of MGAF. Higher deposition of MMAE is also observed in vivo after up-regulation of FR expression level in tumor xenografts, induced by the prior administration of the Dexa/VPA combination. In this model, MGAF/Dexa/VPA combined therapy results in an 81% inhibition of tumor growth compared to the control group, while MGAF used in monotherapy is inefficient. Since Dexa and VPA are currently used in humans, this finding could be of great interest for further development of folate-drug conjugates, in particular for those that are presently under clinical investigation.

New cytotoxic analogues of annonaceous acetogenins.

A series of new acetogenin analogues incorporating a central catechol moiety instead of the tetrahydrofuran ring(s) have been prepared and tested against L1210 leukemia cells. Although less potent than bullatacinone, which has the same terminal lactone, these compounds display interesting cell cycle effects.

Synthesis and cytotoxic activity of acetogenin analogues.

A set of 16 new simplified analogues of acetogenins has been designed based on: (i) the replacement of the bis THF moiety of these natural products by an ethylene glycol bis ether unit; (ii) the introduction of different lipophilic side chains (alkyl, aryl, dialkylamino, O-cholesteryl); (iii) the presence of the same terminal isolactone. In vitro cytotoxic activity against L1210 leukemia is reported.

Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy.

A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.

Prodrugs of anthracyclines for chemotherapy via enzyme-monoclonal antibody conjugates.

New prodrugs of daunorubicin, 1c, 1e and 2c, including a galactopyranosyl residue linked to the N-3' of the daunosaminyl moiety through substituted o- or p-benzyloxycarbonyl groups were synthesized. Their low cytotoxicity and high stability in plasma fulfil the conditions for antibody-directed enzyme prodrug therapy (ADEPT). Enzymatic hydrolysis using alpha-D-galactosidase gives rise to daunorubicin by subsequent self-elimination of the spacers. However, elimination clearly depends on the aromatic substitution pattern, as demonstrated especially by comparison with non-substituted analogues.

[Lipoma of the colon]. / Les lipomes du côlon.

Two cases of submucosal lipoma of the transverse colon are described with their anatomoclinic characteristics and the different aspects of their treatment. These lesions occur with the maximum frequency in the fifth or sixth decades of life and are mostly found in women. 18 per cent of them are located on the transverse colon. In 10 per cent of the cases, the lipomas are multiple. Their clinical symptoms are directly related to their size. Abdominal pains, rectal bleedings and signs of obstruction are the most common symptoms. Thanks to barium enema and endoscopic examination, they are usually diagnosed preoparatively and may be excised through a colotomy in the majority of cases, or by endoscopic removal.

[Diastatic perforations of the colon of neoplastic origin. Apropos of 15 cases]. / Perforations diastatiques du côlon d'origine néoplasique. A propos de 15 observations.

Typical findings in 15 patients with diastatic perforation of colon due to neoplasm were the preferential site of perforation in cecum and of obstruction in left colon, and the very poor prognosis with postoperative mortality of approximately 50%. The very varied therapeutic attitude is the result of difficulties in deciding which operative procedure is required. When perforation and obstruction are adjacent, a fairly rare observation, radical excision of the segment of intestine involved appears the most suitable operation. When the two lesions are separated then in addition to conservative treatment (suture of perforation and anus bypass or cecostomy alone or combined with colon bypass) an increasing number of authors recommend initial subtotal colectomy.

[Factors in recurrence of perforated duodenal ulcer after simple suture. Therapeutic deductions]. / Les facteurs de récidive des ulcères duodénaux perforés après suture simple. Déductions thérapeutiques.

Objective predisposing factors leading to relapse after simple suture for perforated duodenal ulcer were evaluated by a retrospective study of 80 cases. Statistical analysis showed 3 main factors to be involved: age under 45 years, presence of a previous ulcer ano smoking, and these were attributed a coefficient of severity. A simple method will enable a population at high risk of recurrence to be selected, for which immediate radical treatment can be applied when vital risk factors, also analyzed in this study, are lacking.