Can combination metronomic therapy overcome chemoresistance in cholangiocarcinoma: A literature review.

Cholangiocarcinoma (CCa) is relatively resistant to chemotherapy as well as radiation therapy, and complete resection is the main curative therapy for these patients. The prognosis for patients with unresectable intrahepatic CCa (iCCa) is extremely poor. A 55‑year‑old woman presented at our hospital with abdominal pain. After evaluation, she was diagnosed to have multifocal iCCa. She did not opt for standard chemotherapy and therefore received oral metronomic therapy with a combination of celecoxib, etoposide, and cyclophosphamide for a total of 30 months. Presently, she is 57 months post diagnosis and 27 months post cessation of all treatment and continues to be in complete radiological remission. In the present report, we review the literature and discuss whether metronomic scheduling of biologic agents and anticancer drugs will be able to overcome chemoresistance and improve the outcome in cholangiocarcinoma. References for the review were identified through searches of Pubmed for the last 10 years as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.

Micropropagation and production of camptothecin form in vitro plants of Ophiorrhiza mungos

Objective: To explore the biotechnological potential of Ophiorrhiza mungos for micropropagation and camptothecin (CPT) production from in vitro grown plants.Methods: Surface sterilized explants of O. mungos were transferred aseptically in MS media containing various combinations of phytohormones for callus initiation and multiple shoot proliferation. The content of CPT was quantified in the methanolic extract of O. mungos plants and in in vitro grown plants by using high performance liquid chromatography (HPLC). Results: Maximum fresh weight and dry weight biomass of O. mungos callus was obtained from MS medium supplemented with IAA (2 ppm)+ BAP (2 ppm) + GA (1 ppm). The maximum shoot proliferation (25) and elongation (6.5 cm) was found in MS medium supplemented with Picloram + Thidiazuron + Gibberellic Acid in 1:2:1 ratio after four weeks of incubation. The maximum content of CPT (0.0768 % w/w) was found in wholein vitro plants whereas the minimum CPT was observed in adventitious buds (0.0026 % w/w) as compared to the naturally grown O. mungos plants (0.0030% w/w).Conclusions: Present findings indicate that O. mungos plants respond favourably for in vitro propagation and also produce higher amount of CPT as compared to naturally grown plants.

Dose-dependent response of central dopaminergic systems to metoclopramide in mice.

Metoclopramide (5 to 40 mg/kg, i.p.) induces catalepsy and antagonised apomorphine induced cage climbing behaviour in mice. This further indicate its postsynaptic striatal and mesolimbic D 2 dopamine (DA) receptor blocking activity. Metoclopramide at 1.25 and 2.5 mg/kg, i.p. induced stereotyped cage climbing behaviour in mice. Pretreatment with haloperidol and alpha-methyl-p-tyrosine significantly antagonised metoclopramide (1.25 and 2.5 mg/kg)-induced stereotyped cage climbing behaviour. Metoclopramide at these doses induces stereotyped cage climbing behaviour by releasing DA from the mesolimbic dopaminergic neurons with resultant activation of the postsynaptic mesolimbic D 2 DA receptors by the released DA. DA releasing action of metoclopramide (1.25 and 2.5 mg/kg, i.p.) and the subsequent induction of the stereotyped cage climbing behaviour by these doses of metoclopramide is explained on the basis of selective blockade of the presynaptic D 2 DA autoreceptors by these doses of metoclopramide.

Effects of pentazocine on dopamine-dependent behaviours in mice.

Pentazocine, a kappa opioid receptor agonist, induced catalepsy in mice suggesting thereby that it might possess postsynaptic striatal D 2 dopamine (DA) receptor blocking activity. However, our other findings, that pentazocine pretreatment did not antagonise the cage climbing behaviour induced by the directly acting DA agonist apomorphine in mice and actually potentiated the stereotyped behaviour induced by the indirectly acting DA agonist methamphetamine in mice, indicate that pentazocine does not possess postsynaptic striatal and mesolimbic D 2 DA receptor blocking activity. Pretreatment with naloxone, an antagonist of opioid receptors, antagonised pentazocine-induced catalepsy. This suggests the possible involvement of opioid mechanisms in the induction of catalepsy by pentazocine in mice.

Involvement of dopaminergic mechanisms in racemate pentazocine induced stereotyped behaviour in rats.

Racemate pentazocine was found to induce stereotyped behaviour (SB) in rats. Pretreatment with haloperidol and alpha-methyl-p-tyrosine significantly antagonised dl-pentazocine induced SB. This indicates that dl-pentazocine induces SB by releasing dopamine (DA) from the nigrostriatal and mesolimbic dopaminergic neurones with resultant activation of the postsynaptic striatal and mesolimbic D2 DA receptors by the released DA. However, pretreatment with naloxone failed to significantly modify dl-pentazocine induced SB indicating thereby that opioid mechanisms are not involved in the DA releasing action of dl-pentazocine. Our findings are explained on the basis of recent reports that the d-isomer of pentazocine releases DA by stimulating sigma receptors located on the nigrostriatal and mesolimbic dopaminergic neurones.