Paclitaxel Against Cancer: A new trademarked drug.

 

Avinash B Thalkari1*, Pawan N Karwa2, Krushna K Zambare1, Nagesh S Tour1, Priyanka S Chopane1

1SBSPM’s B Pharmacy College, Ambajogai-431517, Maharashtra

2Gurukrupa Institute of Pharmacy (Degree), Majalgaon- 431131

*Corresponding Author E-mail: avinashthalkari@rediffmail.com

 

ABSTRACT:

Cancer is a do or die situation or thecondition. As we know although it has been deeply studied in the field of medical research, not all attempts have been fulfilled. More than half the people who have received a treatment on cancer receive chemotherapy. One such effective discovery leads to Paclitaxel, a Pacific Yew tree isolate. In this reviewan attempthas been made to a few advancements in cancer treatment using Paclitaxel after its discovery. In this reviewa practice has been done to discuss the various researchesusingPaclitaxel and its efficacy against various types of cancers and stresses on the need for the research in the field of Cancer Chemotherapy.

 

KEYWORDS: Paclitaxel, Cancer, Chemotherapy, Antimicrotubule, Taxane.

 

 


I] INTRODUCTION:

Cancer may be defined as a group of cellsthat undergoes unregulated growth, and forms a mass but are distributed diffusely1.In the past decates of the years the antimicrotubule agent have played an crucial in the treatment of anti canceragents. Significantly contributing to cure thediseases includingsuch as malignant lymphomas, leukamias also the germs cells of the cancer can be treated. The search for new antimicrotubule agents during the past few decades has received less scope than expected. Paclitaxel, was extracted as early in  the late 1960s from the bark of the Pacific Yew Taxusbrevifolia, is the first compound with a taxene ring which shown to possess antitumor activity2,because of the insufficiency of the drug, the difficulties in its isolation, extraction and formulation, also has been seen in the pastyears.

 

A survey shows that the development of this antitumor agent was initially relatively slow in the past decades of years. Once these problems were solved and after the discovery of its unique mechanism of action, hada tremendous increase in it work. The second drug in this new class of compounds is docetaxel, extracted in late1986 from the needles of the European Yew Taxusbaccata3. Monroe E. Wall and Mansukh C. Wani in 1967 isolated a mitotic inhibitor from the bark of Taxusbrevifolia (northwest Pacific Yew Tree) (Figure 1) and named this compound as Taxol. It was later known that the Taxol was produced from a fungal endophyte when it was grown on semisynthetic media. The fungal endophyte was found to be isolated from the phloem tissue of the Pacific Yew Tree4.Bristol-Myers Squibb Company was the first ever to obtain as well as sell it with the generic code name Paclitaxel andwas sold under the trademark Taxol.Several formulations were later developed in this field by equal ratio of the Paclitaxel with equal con of of albumin, Polycitrateetc.The research shows that 105 among 150 strains belonged to 25 different genera whereas one single remained undetermined and 44 did not showed any reproductive structure in its any of the solid cultures5.

 

Figure 1: A glimpse of Taxus brevifolia bank

 

II] GENERAL PROPERTIES:

·       Drug name: Paclitaxel

·       Synonym(S): benzenepropanoic acid1

·       Common trade name(S): Taxol®, Onxol®

·       Classification: antimicrotubule agent

·       Paclitaxel is a white crystalline powder

·       Its empirical formula is C47H51NO14

 

Molecular weight is nearly about 853.9 units.

It is highly water insoluble.

 

Its melting point was tonoted between 216-217°C6

·       Systemic name: (2𝛼, 5𝛽, 7𝛽, 10𝛽, 13𝛼)-4,10-Diacetoxy-13-{[(2R, 3S)-3- (benzoylamino)-2-hydroxy-3- phenylpropanoyl]oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11- en-2-yl benzoate7.

 

Figure2: Chemical structure

 

Paclitaxel, belongs to the class of taxane drugs, is a diterpenoidpseudo alkaloid with the empirical formula C47H51NO14 and has a corresponding molecular weight of 853.9 g/mol. Paclitaxel consist of two molecules system: a taxane ring with a four membered oxetane side ring at positions C4 and C5 and a homochiral ester side chain at C13. The side chain at C13 plays a beneficial role, as this is the active portion that binds to microtubules, it helps to stabilize the tubulin bundles, and stimulatesdisassembly of microtubules in a guanosine triphosphate (GTP)-independent manner. As a result, cell proliferation is inhibited by halting the cell cycle at the metaphase/anaphase boundary and by the formation of an incomplete metaphaseplate of chromosomes that are induced by the stabilization of the microtubule dynamics. Extensive research has concluded that an intact taxane ring and an ester side-chain are must to study of cytotoxic activity8,9.

 

III] MECHANISM OF ACTION:

Primarily target towardstubulin is the first step of Paclitaxel drug. Researchers have observed that Paclitaxel treated cells have difficulty with the spindle assembly setup, cell division and also chromosome segregation which is in opposing behavior to Colchicine, a drug that targets tubulin.The main difference between Colchicine and Paclitaxel is that Colchicine helps in the inhibitionof the microtubule assembly whereas Paclitaxel stabilizes and helps in the protection of the microtubuleagainst disassembly. At a higher dose, Paclitaxel is known to suppress microtubule towards the minusends for the detachment from centrosomes4,5, 6. The beta-tubulin subunit is known to have the main binding site for Paclitaxel10. Paclitaxel is a taxaninwhich binds to tubulin,which is the protein component of microtubules, simultaneously promoting their assembly and disassembly leading to form stable, nonfunctional microtubules11,12. Although some reported studies indicate that a cross-reactivity rate of 90% between docetaxeland paclitaxel is observed, others suggest it does not occur consistently13,14. Stabilization of microtubules blocks the cells seen in the M phase of the cell cycle, inhibiting cell division and leading to the cell death12Paclitaxel also acts as a radio sensitizing agent by blocking cells in the G2phase14. Paclitaxel is also responsible for the immunosuppressant activity15,16.

 

IV] Pharmacokinetics:

The pharmacokinetic study of paclitaxel includes the Oral absorption as well as its distribution and the metabolism process and lastly the excretion. In few particular cases no data has been yet researched.

 

1)    Oral absorption:

In the oral absorption no specific data was obtained. As in further the results will be known.

 

2)    Distribution:

Biophysically the initial distribution is towards the peripheral components.Thenit is widely distributed into the body fluids along with the tissues.If any small change in the dose is seen it leads to the change peakplasma command leads to the total drug exposure due to saturable nonlinear pharmacokinetics.It does not cross the blood brain barrier.Here the volume of the distribution varies from 67L/m2 for 1-6 hours infusion to 198-688 L/m2 for 24 hours infusion.The distribution leads to plasma protein binding to nearly about 88-98%

 

3)    Metabolism:

It is completely metabolized in the liver, the main site of metabolism. It is done by the CYP 2C8 and CYP 3A4 pathway. The mechanism is still unknown. The main metabolites used in then process are 67% as 6α-hydroxypaclitaxel via CYP 2C8; 37% involves the 3-p-hydroxypaclitaxel and 6α,3-p-dihydroxypaclitaxel via CYP 3A4.

 

4)    Excretion:

The excretion is primo literarily done by the bile. The left over is removed from the urine andsome other left through the feces.

 

5)    Terminal half-life:

The terminal half-lifevaries from dose and infusion time and is about 10 hours17.

 

V] Side Effects:

As we know that all the drugs have some or the other side effects so the main side effects seen in the paclitaxel are as under. The given below table includes adverse events that are noted during drug treatment but may not necessarily have a close relationship with the drug, as the clinical trials are conducted under very specific conditions, the adverse event rates observed does not completely reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials18,19,20,21.

 

Table No. 01. Side effects

ORGAN SITE

SIDE EFFECT

Blood and lymphatic system/ febrile neutropenia

Anemia (62-78%, severe 6-16%)

Leukopenia (86-90%, severe 4-17%)

Neutropenia (87-90%, severe 27-52%); nadir 10-12 days, recovery 15-21 days; may require dose reduction

Thrombocytopenia (6-20%, severe 1-7%); nadir 8-9 days

Cardiac

Bradycardia (3-4%); first 3 h of infusion; see paragraph following Side Effects table           

Cardiovascular events (severe 1-2%); see paragraph following Side Effects table

Ear and Labyrinth

Hearing loss, tinnitus, vertigo, ototoxicity (<1%)

Eye

Optic nerve and/or visual disturbances, photopsia, visual floaters (<1%); generally reversible, may be dose-related

Gastrointestinal

Emetogenic potential: low-moderate

Abdominal pain; with intraperitonealadministration6

Anorexia (25%)1

Constipation (18%)111,17

 

VI] Supply and Storage:

Injection:

According to Healthcare Inc. supplies

·       Paclitaxel as 30 mg, 100 mg, and 300 mg vials in a concentration of 6 mg/mL.

·       Store at room temperature only.

·        Product may precipitate if refrigerated; precipitate redissolves at room temperature.

·       Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 39.1 %(w/v) ethanol. (22)

 

BiolysePharma supplies:

Paclitaxel as 30 mg and 100 mg single dose vials and a 300 mg multi-dose vial in a concentration of 6 mg/mL.

·       Refrigerate.

·       Do not freeze.

·       Potency is not affected when transported or stored for up to 2 months at room temperature.

·       Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 49.7 %(v/v) alcoho11.

 

VII] Uses:

Primary uses:

It is used in the treatment of the following organ cited diseases.

·       Breast cancer

·       Lung cancer, non-small cell

·       Ovarian cancer

·       Kaposi’s Sarcoma

·       Cervical cancer

·       Endometrial cancer

 

Other Uses:

·       Lung cancer, small cell

·       Esophageal cancer

·       Bladder cancer

·       Head and Neck cancer12

 

VIII] Precautions:

Caution:

1.     Preexisting liver impairment may impair elimination of paclitaxel; dose reduction is suggested.

 

Special populations:

1.     The Elderly patients may have more myelosuppression, neuropathy and cardiovascular toxicities as compared to the younger generations.

2.     Patients with AIDS-related Kaposi’s sarcoma may have more hematologic toxicities, infections and febrile neutropenia.

3.     Carcinogenicity: no information was found in the Carcinogenicity.

4.     Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test. Paclitaxel is clastogenic in human lymphocytes in vitro but not in other mammalian in vivo chromosome tests.

 

5.     Fertility: In animal studies, a slightly reduced fertility has been observed, with a decreased pregnancy rates and increased embryo loss in females and testicular atrophy/degeneration in males.

 

6.     Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Paclitaxel has shown to be embryotoxic and fetotoxic effect in the animal studies; soft tissue and skeletal malformations have been reported. Breastfeeding is not instructed to the potential secretion into breast milk11,13,17.

 

IX] Role of Paclitexal In Inhibiting Various Types of Cancer:

All detailed studies have been done in the field of cancer treatment, especially in the use of various chemotherapeutic agents. Nanoparticle assisted chemotherapeutic drug delivery has been used as a side option as it have the therapeutic effectiveness. Studies on metastatic breast cancer demonstrates the inhibition of metastasis by co-delivering chemotherapeutic agent Paclitaxel and twist shRNA via complex nanoparticles thus by the affectively achieving cellular uptake, RNA 47 interference and inhibited metastasis23. Administration of Paclitaxel loaded expansile nanoparticles (pax-eNP) at the time of cytoreductivesurgeryeffectivelyhelp to reduce the local tumor recurrence in Ovarian Carcinoma24. Chemotherapeutic nanoparticles providefree drugs as they achieve slower clearance and accuracy in target delivery 25. However, chemoresistance has been observed in various cancer types, including breast, lung, prostate, ovarian, and neck carcinomas. Nanoparticles conjugated with Paclitaxels can also be delivered as nanomicelles and these formulations can be simply uptaken by intracellular endocytosis which showed higher rate of efficiency in drug delivery to the target tumor when is compared with other formulationspresent in the market26,27. Multiwall carbon nanotubes have also been used as an alternative potential drug delivery systems where Paclitaxel has been conjugated with poly citric acid. Use of an inhibitor against an activating mutation of signaling molecule in combination with a standard chemotherapeutic agent such as Paclitaxel showed synergistic activity in mutant human endometrial cancer cell lines28. A study performed to evaluate the cytotoxic effects of Paclitaxel in combination with Etoposide in Osteosarcoma cells to thermochemotherapy showed that the apoptosis inducing capacity of the drug combination was stronger than the effect of drugs whenused individually29. A study demonstrates an enhanced Paclitaxelactivity in conjugation with gelomulide K, a caspase-independent cell death inducing agent providing an insight into the development of new caspase-independent cell death-inducing agents (30). Involvement of many target signal transducers as targets to inhibit metastasis bya chemotherapeutic target is being studied for their ability to mutate, activate or inhibit to suppress the tumor (31-36). Despite various efforts, multiple myeloma remains incurable. Thus in most cases, combination of chemotherapeutic drugs have been used in order to increase the efficiency. Mostly Paclitaxel synergized with farnesyltransferase inhibitor R115777 (Zarnestra) was found effective enough to induce G2/M cell cycle arrest37.Due to hypersensitivity reactions and altered pharmacokinetics of Paclitaxel in combination withCremophor EL, ABI-007, a Cremophor-free, albumin-stabilized, nanoparticle paclitaxel formulation was used and found to have less toxicity in comparison to Cremophor-containing Paclitaxel in mice (38). In a study conducted, use of an oral paclitaxel formulation based onthiolatedpolycarbophil showed significant improved paclitaxel plasma levels and reduced tumor growth (39). Paclitaxel in various studies is showed as effective anticancer agent against lung, breast, ovarian, leukopenia and liver cancer40-45. It is also known to produce macrophage IL-12 in tumor bearing hosts which down regulates the tumor growth significantly by selective dysregulation of IL-12 p40 expression46. It is also known to reduce glycolysis by specific mechanisms47. Paclitaxel has a role in treating various kinds of cancer by targeting tubulin or inducing cell cycle arrest or enhancing the signaling factors or mutating them38-55. Unfortunately the high demand for Taxol from the bark of Pacific yew is a challenging aspect for this new therapeutic weapon56.So the main intension should be on development of the product by chemical/ synthetic methods in order to meet the growing need of this anticancer drug.

 

X] Future Perspective:

In the upcoming decades it will be clear that the taxanedrugs will be a major part as an addition to the presently available classes of drugs seen in the market. Nevertheless, few questions regarding the two presently clinically available representatives need to be answered. For paclitaxel the optimal dose and infusion schedule should be identified, also taking into account patient convenience. Its combination with other drugs also needs to be investigated in detail, in order to be used in future. Partly in view of preliminary data showing important sequence-dependence in vitro as well as in clinical studies. Fordocetaxel, measures to prevent nail toxicity and fluid retention will be essential, and it may be important as well to try to further reduce paclitaxel-related neuro- and cardiac toxic effects. Studies on combinations of docetaxel with other cytotoxic drugs will also be performed in the next few years. Preclinical data on sequence dependencesuch as those now available for paclitaxel have not yet been reported for so it can be new discovery in coming years. As the mechanism of action of these drugs is new, analogue development will undoubtedly be one of the main topics in the upcoming years57.

 

XI) CONCLUSION:

Paclitaxel is a very potent anticancer agent obtained from the Pacific Yew tree bark. It seems to raise its efficacy by having multi targets as described earlier, thus being effective against most cancers. This drug has been studied extensively since 1967, from the time of its discovery till date. The main drawback seems to be the mass production of this drug, which can be resolved by focusing more on either chemical/ microbial synthesis of Paclitaxel for the clinical use.

 

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Received on 29.04.2019         Modified on 20.05.2019

Accepted on 18.06.2019       ©A&V Publications All right reserved

Res.  J. Pharmacognosy and Phytochem. 2019; 11(3):123-128.

DOI: 10.5958/0975-4385.2019.00021.9